Patent Publication Number: US-9889145-B2

Title: Methods to treat infections

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims the benefit of U.S. Provisional Application No. 61/814,983, entitled “Methods to Treat Infections” filed Apr. 23, 2013, which is herein incorporated by reference in its entirety. 
    
    
     U.S. GOVERNMENT RIGHTS 
     This invention was made with U.S. Government support by grant number U54 AI057156 awarded by the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The U.S. Government has certain rights in this invention. 
    
    
     BACKGROUND 
     The present invention relates to a method of treating infections. Some embodiments of the invention include administration of one or more COX inhibitors (e.g., COX-1 or COX-2 inhibitors) to treat infectious diseases. Other embodiments of the invention include administration of one or more COX inhibitors (e.g., COX-1 or COX-2 inhibitors) and administration of one or more antibiotics to treat infectious diseases. 
     U.S. Provisional Application No. 61/794,815 entitled “Efficacy of Cox-2 inhibition in melioidosis” with inventors Lisa A. Morici and Saja Asakrah, filed Mar. 15, 2013, is herein incorporated by reference in its entirety. 
     SUMMARY 
     Some embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal. Other embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to the animal. Certain embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal prior to exposure to the bacterial infectious disease; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal prior to exposure to the bacterial infectious disease. Some embodiments of the invention include methods for prophylactically treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometime these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. Other embodiments of the invention include methods for decreasing a bacterial load of an infecting bacteria in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. Some embodiments of the invention include methods for decreasing PGE-2 production in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. 
     Some embodiments of the inventions disclosed herein include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to the animal. 
     Other embodiments of the inventions disclosed herein include methods for treating a bacterial infectious disease comprising administering a therapeutically effective amount of one or more COX inhibitors (e.g., a COX-2 inhibitor), and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to an animal exposed to the bacterial infectious disease. 
     Still other embodiments of the inventions disclosed herein include methods for decreasing a bacterial load of an infecting bacteria in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal. 
     Further embodiments of the inventions disclosed herein include methods for decreasing PGE-2 production in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal. 
     Additional embodiments of the inventions disclosed herein include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal prior to exposure to the bacterial infectious disease. 
     Other embodiments of the inventions disclosed herein include methods for prophylactically treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal. 
     In certain embodiments, the one or more administering steps are applied to the animal post-exposure to the bacterial infectious disease or prior to exposure to the bacterial infectious disease. Other embodiments include administering a therapeutically effective amount of one or more COX inhibitors not more than about 30 minutes after exposure, not more than about 24 hours after exposure, or not more than about 48 hours after exposure. In some instances, exposure is through contact with a mucous membrane. 
     In some embodiments, the methods can further comprise administering a therapeutically effective amount of one or more antibiotics. For example, the method can further comprise administering a therapeutically effective amount of one or more antibiotics applied to the animal post-exposure to the bacterial infectious disease or prior to exposure to the bacterial infectious disease. In other examples, the method can further comprise administering a therapeutically effective amount of one or more antibiotics selected from Sulfonamides, Cephalosporins, Sulfamethizole, Sulfamethoxazole, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Cefoperazone, Ceftazidime, and Doxycycline. 
     In some embodiments of the invention the method does not comprise administering an antibiotic to the animal. 
     Still other embodiments include administering a therapeutically effective amount of one or more antibiotics that is not optional. 
     In certain aspects, the bacterial infectious disease, when untreated or when treated by one or more antibiotics only, results in one or more of (a) increasing PGE-2 production in the animal, (b) increasing Arg2 expression in the animal, (c) increasing arginase production in the animal, (d) decreasing NO production in the animal, (e) weight loss in the animal, or (f) an increase in the bacterial load of the infecting bacteria in the animal. 
     In other aspects, the bacterial infectious disease, when untreated or when treated by one or more antibiotics only, results in increasing PGE-2 production in the animal, an increase in the bacterial load of the infecting bacteria in the animal, or both. 
     In some embodiments, the bacterial infectious disease is caused by a Gram-negative bacteria or a Gram-positive bacteria. In other embodiments, the bacterial infectious disease is caused by a drug-resistant bacteria or a multidrug-resistant bacteria. In further embodiments, the bacterial infectious disease is caused by a drug-resistant bacteria or a multidrug-resistant bacteria and the bacterial infectious disease results in increasing PGE-2 production in the animal. In other embodiments, the bacterial infectious disease is (a) a mucosal bacterial infection, a  Burkholderia  infection, a  Mycobacterial  infection, an  Enterococcus  infection, melioidosis, or tuberculosis, or (b) an infection caused by  Burkholderia pseudomallei, Burkholderia mallei, Burkholderia thailandensis, Mycobacterium tuberculosis, Francisella tularensis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella , or  Shigella flexneri.    
     In certain embodiments, the one or more COX inhibitors is a COX-2 inhibitor. In other embodiments, the one or more COX inhibitors is Lumiracoxib, Etoricoxib, Valdicoxib, Roficoxib, Etodolac, Celecoxib, NS398, or Indomethacin. In some aspects, the dosage of the COX inhibitor is at least about two-fold higher compared to a COX inhibitor dosage for long term usage. 
     In certain embodiments, the bacterial load of the infecting bacteria in the animal decreases by at least about 50% in about 24 hours after starting the treatment. In other embodiments, the method results in one or more of (a) decreasing PGE-2 production in the animal, (b) decreasing Arg2 expression in the animal, (c) decreasing arginase production in the animal, (d) increasing NO production in the animal, (e) a lack of weight loss in the animal, or (f) a decrease in the bacterial load of the infecting bacteria. 
     In other embodiments, the bacterial infectious disease infects, in the animal, one or more of lung, liver, esophagus, stomach, eye, nose, sinus, ear, ear canal, mouth, hand, foot, urethra, or spleen. 
     In some aspects, an antibiotic is not administered to the animal. 
     In other aspects, the animal is not cured of the bacterial infectious disease by an antibiotic(s) only treatment. 
     In certain aspects of the invention, the animal is exposed to the bacterial infectious disease and exposure is through the skin, inhalation, injection, or contact with a mucous membrane. 
     In some embodiments, the manner of administration of one of the one or more COX inhibitors is by pill, liquid, aerosol, intranasal administration, topical administration, or injection. 
     In other embodiments, the manner of administration of the one or more COX inhibitors does not include topical administration of an eye. 
     In yet other embodiments, the manner of administration of one of the one or more antibiotics is by pill, liquid, aerosol, intranasal administration, topical administration, or injection. 
     In still other embodiments, the manner of administration of the one or more antibiotics does not include topical administration of an eye. 
     In other instances, the animal is post-exposure to the bacterial infectious disease. 
     In certain embodiments, the animal displays one or more symptoms of the bacterial infectious disease. In some instances, the animal is diagnosed with the bacterial infectious disease. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the description of specific embodiments presented herein. 
         FIG. 1A  and  FIG. 1B  show mRNA expression fold-change in responses to  Burkholderia thailandensis  (Bt) infection of macrophages. 
         FIG. 2  shows PGE-2 concentration levels in supernatants harvested from macrophages infected with  Burkholderia thailandensis  and  Burkholderia pseudomallei  (Bp). (A) Levels of PGE-2 at two, four, and eight hours post-infection in J774A-1 macrophages infected with Bt; (B) PGE-2 levels at two, four, and six hours post-infection of bone marrow derived macrophages (BMDM) with Bp; and (C) PGE-2 levels at eight and 24 hours post-infection in A549 human lung alveolar epithelial cells in response to Bt infection. *p&lt;0.05, **p&lt;0.01, ***p&lt;0.001. 
         FIG. 3  shows an assessment of the influence of PGE-2 on  Burkholderia intracellular  survival. (A) Bt survival in J774A-1 macrophages pre-treated with NS398 (a selective Cox-2 inhibitor); (B) PGE-2 levels measured in the supernatants of NS398-treated and non-treated macrophages; and (C) Bps survival six hours post-invasion after pre-treatment of BMDM with NS398 with or without the addition of 1 μM of exogenous PGE-2 to the Cox-2 inhibitor pre-treated cells. ***p&lt;0.001 
         FIG. 4  shows the effect of PGE-2 on NO in response to Bt and Bps infection. (A) NO (B) iNOS levels observed after two and four hours post-infection in BMDM, after pre-treatment of macrophages with the Cox-2 inhibitor NS398 and after the addition of 1 μM PGE-2 to NS398-treated macrophages infected with Bt; (C) Arg1 and Arg2 mRNA levels four hours post-exposure to Bps. *p&lt;0.05***p&lt;0.001 
         FIG. 5  shows NO levels and intracellular bacterial survival after inhibition of arginase with nor-NOHA. (A), (B) Intracellular survival in nor-NOHA treated cells two and six hours post-infection with Bt and Bp respectively. (C), (D) NO levels in nor-NOHA treated cells two and four hours post-infection with Bt and Bp respectively. ***p&lt;0.001 
         FIG. 6  shows PGE-2 levels in lung homogenates of BALB/c mice obtained at 24, 48, and 72 hours post-infection with a lethal dose of Bt (10 6  cfu). **p&lt;0.01 
         FIG. 7  shows PGE-2 levels in lung homogenates of BALB/c mice obtained at 24, 48, and 72 hours post-infection with a lethal dose of Bps (3×10 3  cfu). *p&lt;0.05 
         FIG. 8  shows Arg2 and iNOS expression 48 and 72 hours post-infection in the lungs of Bt-infected mice. ***p&lt;0.001 
         FIG. 9  shows a Western blot analysis of lung and liver tissue for Arg2 levels in mice treated with 80 mg/kg Celecoxib compared to mock-treated mice 48 hours after pulmonary Bt infection. 
         FIG. 10  shows immunohistochemical staining analyses of Arg2 in the lungs of mice treated with 80 mg/kg Celecoxib and mock-treated infected mice and untreated uninfected mice. 
         FIG. 11  shows urea levels in the lungs of uninfected mice, mock-treated infected mice and infected mice treated with 80 mg/kg Celecoxib. *p&lt;0.05 
         FIG. 12  shows differences in IL-1α, IL-6 and KC in the lungs of mock-treated mice and mice treated with 80 mg/kg Celecoxib 48 hours post-infection with Bt. ***p&lt;0.001 
         FIG. 13 .  B. pseudomallei  rapidly induces COX-2 and PGE-2 production by macrophages.  FIG. 13A . Bone-marrow derived macrophages (BMDM) were treated with viable  B. thailandensis  (Bt),  B. pseudomallei  (Bp) or heat-inactivated Bp (iBp) at MOI 1 and COX-2 mRNA expression was measured by RT-PCR.  FIG. 13B . COX-2 enzyme was detected by Western blot in BMDM infected with Bp at MOI 1.  FIG. 13C . BMDM were treated with Bp at MOI 0.1 or 1 and iBp at MOI 1 and PGE-2 was measured in culture supernatants by ELISA. The data represent biological triplicates per time point. Error bars represent the standard deviation (SD). Statistical significance was determined using a two way ANOVA with Bonferroni post-test. *p&lt;0.05, ***p&lt;0.001. Data is representative of two independent experiments. 
         FIG. 14 . PGE-2 promotes  B. pseudomallei  intracellular survival. BMDM were incubated in the presence or absence of NS398 (100 μM)+/−PGE-2 (1 μM) for 30 minutes then infected with Bps at MOI 1.  FIG. 14A  shows percent intracellular survival of Bps.  FIG. 14B  shows corresponding nitrite levels in BMDM supernatants. The data represent biological triplicates per time point. Error bars represent the SEM. Statistical significance was determined using a two way ANOVA with Bonferroni post-test. *p&lt;0.05, ***p&lt;0.001. Data is representative of two independent experiments. 
         FIG. 15 . Arginase 2 enhances  B. pseudomallei  survival in macrophages. BMDM were incubated in the presence or absence of NS398 (100 μM)+/−PGE-2 (1 μM) for 30 minutes, then infected with Bps at MOI 1 for 4 hours.  FIG. 15A  shows fold-change in mRNA expression for iNOS, arginase 1 (Arg1) and Arg2 in response to Bps was measured by RT-PCR. Error bars represent the SEM.  FIG. 15B  shows intracellular survival of Bps in BMDM pre-treated with 100 μM nor-NOHA for 30 minutes.  FIG. 15C  shows corresponding nitrite production by Bps-infected cells in the presence or absence of nor-NOHA. The data represent biological triplicates per time point. Error bars represent the SEM. Statistical significance was determined using a two way ANOVA with Bonferroni post-test. ***p&lt;0.001. Data is representative of two independent experiments. 
         FIG. 16 . Lung PGE-2 increases in a time-dependent manner after pulmonary challenge with  B. pseudomallei . BALB/c mice were infected intranasally with 3×10 3  cfu of Bps and serially sacrificed between 0 (pre-challenge) and 72 hours post-infection (n=3 per timepoint). Animal weight was recorded daily and PGE-2 was measured in total lung homogenates by ELISA. Error bars represent the SEM. *p&lt;0.05 compared to 0h timepoint as determined by one way ANOVA. Data is representative of two independent experiments. 
         FIG. 17 . COX-2 inhibition provides protection against lethal pulmonary melioidosis. BALB/c mice (n=8 per group) were infected with 3×10 3  cfu (4 LD50) of Bps 1026b intranasally. Three hours post-exposure, mice were administered 15 mg/kg of COX-2 inhibitor (NS398) or DMSO (Mock treatment) intraperitoneally, then again daily for two consecutive days. Survival was monitored for 10 days. Statistical significance was determined using Kaplan Meier analysis. p&lt;0.0001. Data is representative of two independent bacterial challenge experiments. 
         FIG. 18 . Lung inflammation is reduced in COX-2 treated mice infected with  B. thailandensis . BALB/c mice were given 15 mg/kg COX-2 inhibitor (Celecoxib) or mock control and challenged concurrently with 3 LD50  B. thailandensis  by intranasal inoculation. Animals were sacrificed at 48 hours post-infection and lungs were stained with H&amp;E (Hematoxylin and eosin stain). Arrow denotes abundant accumulation of inflammatory cells in mock-treated infected mice. Images obtained at 40× magnification. 
         FIG. 19 . COX-2 inhibition reduces lung PGE-2 and tissue bacterial burdens in  B. thailandensis -infected mice. BALB/c mice were given 80 mg/kg Celecoxib or a mock control and infected i.n. with 3LD50  B. thailandensis . At 48 hours post-infection, mice were sacrificed and lung ( FIG. 19A ), liver ( FIG. 19B ), and spleen ( FIG. 19C ) homogenates plated to determine bacterial cfu. In  FIG. 19D , using ELISA assays, PGE-2 was measured in lung homogenates of mock, Celecoxib-treated and DMSO-treated (uninfected) mice. *p&lt;0.05 by Mann-Whitney test. shows bacterial burdens in (A) lung, (B) liver, and (C) spleen 48 hrs post-infection in Celecoxib-treated and DMSO (mock)-treated mice; (D) PGE-2 level in the lungs of mock, Celecoxib-treated and DMSO-treated mice. 
         FIG. 20 . Arg2 is expressed in the lungs of  B. pseudomallei -infected mice and decreases upon COX-2 inhibition. Arg1 and Arg2 expression was examined by Western blot in lung homogenates of uninfected and Bps-infected mice (n=3 per group) treated with 15 mg/kg NS398 or mock control. Mouse liver extract and mouse Arg2-transfected 293T cell lysate were used as positive controls for Arg1 and Arg2 respectively. β-actin was used as a loading control and for normalization in densitometry analysis using the ImageJ program: &lt;&lt;http://rsb.info.nih.gov/ij/&gt;&gt;. Statistical significance was determined using one-way ANOVA with Bonferroni post test. 
       ***p&lt;0.001. 
         FIG. 21 . Exogenous PGE-2 reduces IFN-γ and IL-2 production by stimulated CD4+ T-cells ( FIG. 21A ). Supernatant from Bp82-infected RAW macrophages reduces IFN-γ and IL-2 production by stimulated CD4+ T-cells ( FIG. 21B ). *p&lt;0.05, **p&lt;0.01, ***p&lt;0.001, ****p&lt;0.0001 
         FIG. 22 . COX-2 inhibition in  B. pseudomallei  infected mice.  FIG. 22A  shows that COX-2 inhibition reduces PGE-2 in lung tissue.  FIG. 22B  shows that COX-2 inhibition reduces PGE-2 in stomach tissue.  FIG. 22C  shows that COX-2 inhibition suppresses growth of  B. pseudomallei  in lung tissue.  FIG. 22D  shows that COX-2 inhibition suppresses growth of  B. pseudomallei  in stomach tissue. 
     
    
    
     DETAILED DESCRIPTION 
     Some embodiments of the present invention include methods to treat an infectious disease (e.g., bacterial) comprising administering to an animal an amount (e.g., a therapeutically effective amount) of one or more COX inhibitors; in some embodiments, the methods can further include (e.g., optionally) administering an amount (e.g., a therapeutically effective amount) of one or more antibiotics. In some instances, the administration of a COX inhibitor, an antibiotic, or both are applied to the animal post-exposure or prior to exposure to the bacterial infectious disease. In some embodiments, the animal will be exposed to a bacterial infectious disease after one or more administrations of the COX inhibitor, after one or more administrations of the optional antibiotic, or after one or more administrations of both. In other embodiments, the animal will not be exposed to a bacterial infectious disease. 
     As used herein, the term “treating” (and its variations, such as “treatment”) is to be considered in its broadest context. In particular, the term “treating” does not necessarily imply that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition (e.g., bacterial infection or effects thereof), decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition (e.g., bacterial infection or effects thereof). As used herein, reference to “treating” an animal includes prophylaxis (e.g., pre-exposure prophylaxis or post-exposure prophylaxis). 
     Some embodiments of the invention encompass a method for decreasing a bacterial load of an infecting bacteria in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal. 
     Other embodiments of the invention encompass a method for decreasing PGE-2 production in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein one or both administering steps are applied to the animal. 
     Still other embodiments of the invention encompass a method for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to an animal that displays one or more symptoms of the bacterial infectious disease. 
     Some embodiments of the invention encompass a method for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to an animal that is diagnosed with the bacterial infectious disease. 
     Some embodiments of the invention encompass a method for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to an animal post-exposure to the bacterial infectious disease. 
     Certain embodiments of the invention encompass a method for prophylactically treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics. In some embodiments of this prophylactic treatment, the animal will be exposed to a bacterial infectious disease after one or more administrations of the COX inhibitor, after one or more administrations of the optional antibiotic, or after one or more administrations of both. In other embodiments of this prophylactic treatment, the animal will not be exposed to a bacterial infectious disease. 
     Some embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal. Other embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors, and optionally administering a therapeutically effective amount of one or more antibiotics, wherein the administering steps are applied to the animal. Certain embodiments of the invention include methods for treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal prior to exposure to the bacterial infectious disease; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal prior to exposure to the bacterial infectious disease. Some embodiments of the invention include methods for prophylactically treating a bacterial infectious disease in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometime these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. Other embodiments of the invention include methods for decreasing a bacterial load of an infecting bacteria in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. Some embodiments of the invention include methods for decreasing PGE-2 production in an animal comprising administering a therapeutically effective amount of one or more COX inhibitors to the animal; sometimes these methods can further comprise administering a therapeutically effective amount of one or more antibiotics to the animal. 
     In certain embodiments, the administration of a COX inhibitor takes place not more than about 7 days after exposure, not more than about 72 hours after exposure, not more than about 48 hours after exposure, not more than about 24 hours after exposure, not more than about 18 hours after exposure, not more than about 15 hours after exposure, not more than about 12 hours after exposure, not more than about 9 hours after exposure, not more than about 6 hours after exposure, not more than about 4 hours after exposure, not more than about 3 hours after exposure, not more than about 2 hours after exposure, not more than about 60 minutes after exposure, not more than about 30 minutes after exposure, not more than about 10 minutes after exposure, or not more than about 5 minutes after exposure. In some instances, administration of a COX inhibitor (e.g., a COX-2 inhibitor) post-exposure can be no more than about 1 minute, about 1 minute, about 5 minutes, about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 6 months, about 9 months, about 1 year, about 2 years, about 5 years, about 10 years or not less than about 10 years, after exposure. In some instances, administration of a COX inhibitor (e.g., a COX-2 inhibitor) prior to exposure can be no more than about 1 hour, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or not less than 2 months, before exposure. In some instances, the amount of time prior to exposure is informed by the half-life (i.e., the amount of time it takes for the animal&#39;s blood plasma concentration of the COX inhibitor to decrease by half) of a COX inhibitor (e.g., a COX-2 inhibitor or a COX-1 inhibitor) being administered; for example, administration of a COX inhibitor (e.g., a COX-2 inhibitor) can be no more than about 1 half-life, about 1 half-life, about 2 half-lives, about 3 half-lives, about 4 half-lives, about 5 half-lives, about 6 half-lives, about 7 half-lives, about 8 half-lives, about 9 half-lives, about 10 half-lives, or about 20 half-lives of the COX inhibitor, before exposure. 
     In certain embodiments, a COX inhibitor can inhibit one or more activities of one or more isozymes of COX (prostaglandin-endoperoxide synthase) (e.g., COX-1, COX-2, and/or COX-3). In some embodiments, a COX inhibitor can include COX-2 inhibitors, COX-1 inhibitors, or combinations thereof. In some embodiments, the one or more COX inhibitors are selected from but not limited to 4,5-Bis(4-methoxyphenyl-2-[(1-methylpiperazin-4-yl)carbonyl]thiazole, HCl; 4-Amino-(N-(4-cholorophenyl)-N-methyl)benzenesulfonamide); (Methyl [5-methylsulfonyl-1-(4-chlorobenzyl)-1H-2-indolyl]carboxylate); (4-[(5-Difluoromethyl-3-phenyl)-4-isoxazolyl]benzenesulfonamide); (N-(5-Acetyl-2-piperidinophenyl)-N′-(2,5-dichlorophenyl)thiourea); (5-(4-Methoxyphenyl)-3,7-dimethyl-4,5-dihydroisoxazolo[4,5-d]pyridazin-4-one); (4′-Acetyl-2′-(2,4-Difluorophenoxy)methanesulfonanilide); Diclofenac (4′-Hydroxy-(2-R(2′,6′-Dichloro-4′-hydroxy)phenyl)amino]benzeneacetic Acid)); Diclofenac Sodium ((2-[(2,6-Dichlorophenyl)amino]benzeneacetic Acid, Sodium)); DuP-697 ((5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)thiophene)); Ebselen ((2-Phenyl-1,2-benzisoselenazol-3(2H)-one)); Flurbiprofen ((±)-2-Fluoro-a-methyl[1,1′-biphenyl]-4-acetic Acid)); (±)-Ibuprofen; Indomethacin (1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid); Indomethacin Ester (4-Methoxyphenyl-(1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid, 4-Methoxyphenyl Ester); Kaempferol ((3,4′,5,7-Tetrahydroxyflavone)); MEG Hydrochloride ((Mercaptoethylguanidine, HCl)); Meloxicam ((4-Hydroxy-2-methyl-N-(5-methyl-2-thiazoyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide)); NS398 ((N-(2-Cyclohexyloxy-4-nitrophenyl)methane sulfonamide; Parthenolide (e.g., from the plant  Tanacetum parthenium ); Pterostilbene, (e.g., from the tree  Pterocarpus marsupium )(trans-3,5-Dimethoxy-4′-hydroxystilbene); Radicicol (e.g., from the fungus  Diheterospora chlamydosporia ); Resveratrol (trans-3,4′,5-Trihydroxystilbene); SC-560 ((5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole); Sodium Salicylate; Sulindac Sulfide (((Z)-5-Fluoro-2-methyl-1-[p-(methylthio)benzylidenelindene-3-acetic Acid)); and Sulindac Sulfone (((Z)-5-Fluoro-2-methyl-1-[p-(methylsulfonyl) benzylidene]indene-3-acetic Acid). In other embodiments, the one or more COX inhibitors can be extracts (e.g., using one or more solvents such as, ethanol, water, propanol, methanol or others) of certain organisms such as plants, trees, fungi, including but not limited to  Tribulus terrestris, Tanacetum parthenium, Pterocarpus marsupium , and  Diheterospora chlamydosporia.    
     In other embodiments, the one or more COX inhibitors can be a COX-2 inhibitor selected from but not limited to Lumiracoxib ({2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}acetic acid); Etoricoxib (5-chloro-6′-methyl-3-[4-(methylsulfonyl)phenyl]-2,3′-bipyridine); NS398 ((N-(2-Cyclohexyloxy-4-nitrophenyl)methanesulfonamide; Valdicoxib (4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide); Roficoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one); Etodolac ((RS)-2-(1,8-Diethyl-4,9-dihydro-3H-pyrano [3,4-b]indol-1-yl)acetic acid); Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide); and Indomethacin (2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid. 
     In still other embodiments, the one or more COX inhibitors can be an NSAID (Non Steroidal Anti Inflammatory Drug). NSAIDs can include but are not limited to Ibuprofen, Aspirin, Ketoprofen, Sulindac, Naproxen, Etodolac, Fenoprofen, Diclofenac, Flurbiprofen, Ketorolac, Piroxicam, Indomethacin, Mefenamic Acid, Meloxicam, Nabumetone, Oxaprozin, Ketoprofen, Famotidine (e.g., in combination with ibuprofen), Meclofenamate, Tolmetin, and Salsalate. 
     In certain embodiments, the method of treatment (e.g., by administration of the COX inhibitor alone or with antibiotics) results in one or more of (a) reducing PGE-2 production in the animal, (b) decreasing Arg2 expression in the animal, (c) decreasing arginase production in the animal, (d) increasing NO production in the animal (e) increasing leukocyte activation, (f) increasing macrophage microbicidal activity, (g) increasing NK cell function, (h) up-regulation of cell-mediated immunity, (i) lack of weight loss in the animal, or (j) a reduction in the bacterial load of the infecting bacteria. A modulation (e.g., an increase or a decrease) of any of the above in the animal can be a result of such a modulation in one or more organs in the animal. A reduction in PGE-2 production can be, for example, about 5% reduction, about 10% reduction, about 20% reduction, about 30% reduction, about 50% reduction, about 75% reduction, about 80% reduction, about 90% reduction, about 95% reduction, about 99% reduction, about 99.9% reduction, about 99.99% reduction, or about 99.999% reduction. A reduction in bacterial load of the infecting bacteria can be, for example, about 5% reduction, about 10% reduction, about 20% reduction, about 30% reduction, about 50% reduction, about 75% reduction, about 80% reduction, about 90% reduction, about 95% reduction, about 99% reduction, about 99.9% reduction, about 99.99% reduction, about 99.999% reduction, about 99.9999% reduction, or about 99.99999% reduction. A lack of weight loss of the animal can be, for example, any weight gain, zero weight loss, or a weight loss of about 1%, about 2%, about 3%, about 5%, about 6%, about 8%, about 10%, no more than about 10%, no more than about 5%, or no more than about 1%. 
     In certain embodiments, the one or more antibiotics can be selected from, but are not limited to Aminoglycosides (e.g., Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Streptomycin, Tobramycin); Cephalosporins, First Generation (e.g., Cefacetrile (cephacetrile), Cefadroxil (cefadroxyl), Cefalexin (cephalexin), Cefaloglycin (cephaloglycin), Cefalonium (cephalonium), Cefaloridine (cephaloradine), Cefalotin (cephalothin), Cefapirin (cephapirin), Cefatrizine, Cefazaflur, Cefazedone, Cefazolin (cephazolin), Cefradine (cephradine), Cefroxadine, Ceftezole); Cephalosporins, Second Generation (e.g., Cefaclor, Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil (cefproxil), Cefuroxime, Cefuzonam); Cephalosporins, Third Generation (e.g., Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Cefoperazone, Ceftazidime); Cephalosporins, Fourth Generation (e.g., Cefclidine, Cefepime, Cefluprenam, Cefoselis, Cefozopran, Cefpirome, Cefquinome); Cephalosporins, Not Classified (e.g., Cefaclomezine, Cefaloram, Cefaparole, Cefcanel, Cefedrolor, Cefempidone, Cefetrizole, Cefivitril, Cefmatilen, Cefmepidium, Cefovecin, Cefoxazole, Cefrotil, Cefsumide, Cefuracetime, Ceftioxide); Carbapenems (e.g., Imipenem, Imipenem/cilastatin, Doripenem, Meropenem); Quinolone Antibiotics, First Generation (e.g., Flumequine, Nalidixic acid, Oxolinic acid, Piromidic acid, Pipemidic acid, Rosoxacin); Quinolone Antibiotics, Second Generation (e.g., Ciprofloxacin, Enoxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, Ofloxacin, Pefloxacin, Rufloxacin); Quinolone Antibiotics, Third Generation (e.g., Balofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Pazufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin); Quinolone Antibiotics, Fourth Generation (e.g., Besifloxacin, Clinafloxacin, Gemifloxacin, Sitafloxacin, Trovafloxacin, Prulifloxacin); Macrolide Antibiotics (e.g., Azithromycin, Erythromycin, Clarithromycin, Dirithromycin, Roxithromycin and Ketolides (e.g., Telithromycin)); Penicillins (e.g., Amoxicillin, Ampicillin, Bacampicillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Pivampicillin, Pivmecillinam, Ticarcillin); Sulfonamides (e.g., Sulfamethizole, Sulfamethoxazole, Sulfisoxazole, Trimethoprim-Sulfamethoxazole); Tetracycline Antibiotics (e.g., Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, and Glycylcyclines (e.g., Tigecycline)); Other Antibiotics (e.g., Vancomycin, Metronidazole, Tinidazole, Nitrofurantoin, Chloramphenicol, and Oxazolidinones (e.g., linezolid, eperezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)—N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)—N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride and N-[[(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), and Rifamycins (e.g., Rifampin, Rifabutin, Rifapentine), and Lincosamides (e.g., Clindamycin, Lincomycin), and Streptogramins (e.g., Pristinamycin, Quinupristin/dalfopristin); and still other antibiotics (e.g., Lipopeptides, Fluoroquinolone, Lipoglycopeptides, Cephalosporin (5th generation), Macrocyclics). 
     In certain embodiments, the one or more antibiotics does not include an oxazolidinone drug. In other embodiments, the one or more anitibiotic does not include one or more of (e.g., does not include any of the following) linezolid, eperezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)—N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)—N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride, or N-[[(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. 
     An antibiotic or a combination of antibiotics (and their dosages) can be suitably chosen to optimize treatment. 
     In some instances, administration of the antibiotic post-exposure can be no more than about 1 minute, about 1 minute, about 5 minutes, about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 6 months, about 9 months, about 1 year, about 2 years, about 5 years, about 10 years or not less than about 10 years, after exposure. In some instances, administration of the antibiotic prior to exposure can be no more than about 1 hour, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or not less than 2 months, before exposure. In some instances, the amount of time prior to exposure is informed by the half-life (i.e., the amount of time it takes for the animal&#39;s blood plasma concentration of the antibiotic to decrease by half) of the antibiotic being administered; for example, administration of the antibiotic can be no more than about 1 half-life, about 1 half-life, about 2 half-lives, about 3 half-lives, about 4 half-lives, about 5 half-lives, about 6 half-lives, about 7 half-lives, about 8 half-lives, about 9 half-lives, about 10 half-lives, or about 20 half-lives of the antibiotic, before exposure. 
     In some embodiments, the bacterial infectious disease infects one or more of the following animal organs: Brain, Basal ganglia, Brain stem, medulla, Midbrain, pons, Cerebellum, Cerebral cortex, Hypothalamus, Limbic system, Amygdala, Eyes (or tissues of the eyes), Pineal gland, Pituitary gland, Thyroid gland, Parathyroid glands, Heart, Lungs, Esophagus, Thymus gland, Pleura, Adrenal glands, Appendix, Bladder, Gallbladder, Large intestine, Small intestine, Kidneys, Liver, Pancreas, Spleen, Stomach, Prostate gland, Testes, Ovaries, or Uterus. In certain embodiments, bacterial infectious disease infects one or more of lungs, liver, esophagus, stomach, nose, eyes (or tissues of the eyes), sinuses, ear, ear canals, mouth, hands, feet, urethra, or spleen. In certain embodiments, the bacterial infectious disease does not infect an eye, both eyes, tissues of the eyes, combinations thereof, or any of them. 
     In certain embodiments, the bacteria responsible for the bacterial infectious disease can be, but is not limited to one or more of  Acetobacter aurantius, Acinetobacter baumannii, Actinomyces israelii, Agrobacterium radiobacter, Agrobacterium tumefaciens, Azorhizobium caulinodans, Azotobacter vinelandii, Anaplasma  (e.g.,  Anaplasma phagocytophilum ),  Bacillus  (e.g.,  Bacillus anthracis, Bacillus brevis, Bacillus cereus, Bacillus fusiformis, Bacillus licheniformis, Bacillus megaterium, Bacillus mycoides, Bacillus stearothermophilus, Bacillus subtilis ),  Bacteroides  (e.g.,  Bacteroides fragilis, Bacteroides gingivalis, Bacteroides melaninogenicus  (now known as  Prevotella melaninogenica )),  Bartonella  (e.g.,  Bartonella henselae, Bartonella quintana ),  Bordetella  (e.g.,  Bordetella bronchiseptica, Bordetella pertussis ),  Borrelia burgdorferi, Brucella  (e.g.,  Brucella abortus, Brucella melitensis, Brucella suis ),  Burkholderia  (e.g.,  Burkholderia mallei, Burkholderia pseudomallei, Burkholderia cepacia, Burkholderia tailandensis ),  Calymmatobacterium granulomatis, Campylobacter  (e.g.,  Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Campylobacter pylori ),  Chlamydia  (e.g.,  Chlamydia trachomatis ),  Chlamydophila  (e.g.,  Chlamydophila pneumoniae  (previously called  Chlamydia pneumoniae ),  Chlamydophila psittaci  (previously called  Chlamydia psittaci ),  Clostridium  (e.g.,  Clostridium botulinum, Clostridium difficile, Clostridium perfringens  (previously called  Clostridium welchii ),  Clostridium tetani ),  Corynebacterium  (e.g.,  Corynebacterium diphtheria, Corynebacterium fusiforme ),  Coxiella burnetii, Ehrlichia chaffeensis, Enterobacter cloacae, Enterococcus  (e,g,  Enterococcus avium, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus galllinarum, Enterococcus maloratus ),  Escherichia coli, Francisella tularensis, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus  (e.g.,  Haemophilus ducreyi, Haemophilus influenza, Haemophilus parainfluenzae, Haemophilus pertussis, Haemophilus vaginalis ),  Helicobacter pylori, Klebsiella pneumonia, Lactobacillus  (e.g.,  Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactococcus lactis ),  Legionella pneumophila, Listeria monocytogenes, Methanobacterium extroquens, Microbacterium multiforme, Micrococcus luteus, Moraxella catarrhalis, Mycobacterium  (e.g.,  Mycobacterium avium, Mycobacterium bovis, Mycobacterium diphtheria, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium lepraemurium, Mycobacterium phlei, Mycobacterium smegmatis, Mycobacterium tuberculosis ),  Mycoplasma  (e.g.,  Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma penetrans, Mycoplasma pneumonia ),  Neisseria  (e.g.,  Neisseria gonorrhoeae, Neisseria meningitides ),  Pasteurella  (e.g.,  Pasteurella multocida, Pasteurella tularensis ),  Peptostreptococcus, Porphyromonas gingivalis, Prevotella melaninogenica  (previously called  Bacteroides melaninogenicus ),  Pseudomonas aeruginosa, Rhizobium radiobacter, Rickettsia  (e.g.,  Rickettsia prowazekii, Rickettsia psittaci, Rickettsia quintana, Rickettsia rickettsia, Rickettsia trachomae ),  Rochalimaea  (e.g.,  Rochalimaea henselae, Rochalimaea quintana ),  Rothia dentocariosa, Salmonella  (e.g.,  Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Serratia marcescens ),  Shigella dysenteriae, Shigella flexneri, Staphylococcus  (e.g.,  Staphylococcus aureus, Staphylococcus epidermidis ),  Stenotrophomonas maltophilia, Streptococcus  (e.g.,  Streptococcus agalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus cricetus, Streptococcus faceium, Streptococcus faecalis, Streptococcus ferus, Streptococcus gallinarum, Streptococcus lactis, Streptococcus mitior, Streptococcus mitis, Streptococcus mutans, Streptococcus oralis, Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus rattus, Streptococcus salivarius, Streptococcus sanguis, Streptococcus sobrinus ),  Treponema  (e.g.,  Treponema pallidum, Treponema denticola ),  Vibrio  (e.g.,  Vibrio cholera, Vibrio comma, Vibrio parahaemolyticus, Vibrio vulnificus ),  Wolbachia , or  Yersinia  (e.g.,  Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis ). In some embodiments, the bacteria responsible for the bacterial infectious disease can be a Gram-negative bacteria. In other embodiments, the bacteria responsible for the bacterial infectious disease can be a Gram-positive bacteria. 
     In still other embodiments, the bacterial infectious disease can be but is not limited to one or more of the infections (where the infection is not bacterial in nature, the item listed below indicates that secondary bacterial infectious diseases could result)  Acinetobacter  infections, Actinomycosis, Anaplasmosis, Anthrax,  Arcanobacterium haemolyticum  infection,  Ascariasis, Aspergillosis, Babesiosis, Bacillus cereus  infection, Bacterial pneumonia, Bacterial vaginosis (BV),  Bacteroides  infection,  Balantidiasis, Baylisascaris  infection,  Blastocystis hominis  infection,  Blastomycosis, Borrelia  infection, Botulism (and Infant botulism),  Brucellosis, Burkholderia  infection, Buruli ulcer,  Campylobacteriosis , Cat-scratch disease, Cellulitis, Chagas Disease (American trypanosomiasis),  Chancroid, Chlamydia, Chlamydophila pneumoniae  infection (Taiwan acute respiratory agent or TWAR),  Cholera, Chromoblastomycosis, Clonorchiasis, Clostridium difficile  infection,  Coccidioidomycosis, Cryptococcosis, Cryptosporidiosis, Cutaneous larva migrans  (CLM),  Cyclosporiasis, Cysticercosis, Dientamoebiasis, Diphtheria, Diphyllobothriasis, Dracunculiasis, Echinococcosis, Ehrlichiosis, Enterococcus  infection,  Epidemic typhus, Fasciolopsiasis, Fasciolosis , Fatal familial insomnia (FFI), Filariasis, Food poisoning by  Clostridium perfringens, Fusobacterium  infection, Gas gangrene ( Clostridial myonecrosis ),  Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Granuloma inguinale  (Donovanosis), Group A streptococcal infection, Group B streptococcal infection,  Haemophilus  influenzae infection,  Helicobacter pylori  infection, Hemolytic-uremic syndrome (HUS), HIV, Human ewingii ehrlichiosis, Human granulocytic anaplasmosis (HGA), Human monocytic ehrlichiosis, Hymenolepiasis, Isosporiasis, Kawasaki disease, Keratitis,  Kingella kingae  infection, Kuru, Legionellosis (Legionnaires&#39; disease), Legionellosis (Pontiac fever), Leishmaniasis, Leprosy, Leptospirosis, Listeriosis, Lyme disease (Lyme borreliosis), Lymphatic filariasis (Elephantiasis), Malaria, Melioidosis (Whitmore&#39;s disease), Meningitis, Meningococcal disease, Metagonimiasis, Microsporidiosis, Murine typhus (Endemic typhus),  Mycoplasma pneumonia , Mycetoma, Myiasis, Neonatal conjunctivitis (Ophthalmia neonatorum), Nocardiosis, Onchocerciasis (River blindness), Paracoccidioidomycosis (South American blastomycosis), Paragonimiasis, Pasteurellosis, Pelvic inflammatory disease (PID), Pertussis (Whooping cough), Plague, Pneumococcal infection,  Pneumocystis pneumonia  (PCP), Pneumonia,  Prevotella  infection, Primary amoebic meningoencephalitis (PAM), Psittacosis, Q fever, Rat-bite fever, Rhinosporidiosis, Rickettsial infection, Rickettsialpox, Rocky mountain spotted fever (RMSF), Salmonellosis, Scabies, Schistosomiasis, Sepsis, Shigellosis (Bacillary dysentery), Sporotrichosis,  Staphylococcal  food poisoning,  Staphylococcal  infection, Strongyloidiasis, Syphilis, Taeniasis, Tetanus (Lockjaw), Trichinellosis, Tuberculosis, Tularemia, Ureaplasma urealyticum infection,  Yersinia pseudotuberculosis  infection, Yersiniosis, or Zygomycosis. In certain embodiments, the bacterial infectious disease is a  Burkholderia  infection (e.g., due to  Burkholderia pseudomallei, Burkholderia mallei, Burkholderia cepacia, Burkholderia cepacia complex, Burkholderia thailandensis ), tuberculosis (e.g., due to  Mycobacterium tuberculosis ), or an infection due to  Francisella tularensis, Klebsiella pneumonia, Pseudomonas aeruginosa , or  Shigella flexneri.    
     In some embodiments, the bacterial infectious disease can be a mucosal bacterial infection (e.g., a bacterial infection of a mucous membrane). For example, a mucosal bacterial infection can be a  Burkholderia  infection, a  Mycobacterial  infection, an  Enterococcus  infection, melioidosis, or tuberculosis. In certain instances, a mucosal bacterial infection can be caused by any of the bacteria disclosed herein. In certain embodiments, the mucosal bacterial infection can be caused by  Burkholderia pseudomallei, Burkholderia mallei, Burkholderia thailandensis, Mycobacterium tuberculosis, Francisella tularensis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella , or  Shigella flexneri.    
     In certain embodiments, the bacteria responsible for the bacterial infectious disease can be, but is not limited to one or more of a multidrug-resistant strain of bacteria including, but not limited to,  Burkholderia pseudomallei , Methicillin-resistant  Staphylococcus aureus  (Methicillin-RSA), Vancomycin-Resistant  Enterococcus  (VRE), and Linezolid-Resistant  Enterococcus  (LRE). In some embodiments, the bacteria can be a drug-resistant or multidrug-resistant strain of  Burkholderia pseudomallei, Bacillus subtilis, Escherichia coli, Pseudmonadas aeruginosa, Mycobacterium vaccae, Sporobolomyces salmonicolor, Candida albicans, Penicilluum notatum , and  Mycobacterium tuberculosis . In certain instances, the multidrug-resistant or drug-resistant strain of bacteria can cause an increase in PGE-2 production in the infected animal. Thus, in certain embodiments, methods of using one or more COX inhibitors described herein (plus optionally an antibiotic) may be provided for the treatment of an infection from a drug-resistant strain or multidrug-resistant strain of bacteria. 
     In other embodiments, the untreated bacterial infectious disease can result in death to the animal in an average timeframe of about 30 days, about 20 days, about 10 days, about 5 days, about 4 days, about 3 days, about 2 days, about 1 day, about 18 hours, about 12 hours, about 6 hours, about 3 hours, about 2 hours, or about one hour. 
     In some instances, the bacterial infectious disease does not respond to an antibiotic(s)-only treatment, which can be displayed as one or more of (but not limited to) the following (a) the animal is unable to recover from the infection, (b) the animal dies from the infection, (c) the bacterial load of the infecting bacteria in the animal does not decrease in about 24 hour or in about 48 hours by about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 90%, about 98%, or about 99%. In certain embodiments, the bacterial infectious disease (when untreated or, in some instances, when treated by one or more antibiotics only) can result in one or more of (a) increasing PGE-2 production in the animal, (b) increasing Arg2 expression in the animal, (c) increasing arginase production in the animal, (d) decreasing NO production in the animal (e) decreasing leukocyte activation, (f) decreasing macrophage microbicidal activity, (g) decreasing NK cell function, (h) down-regulation of cell-mediated immunity, (i) weight loss in the animal, or (j) an increase in the bacterial load of the infecting bacteria. A modulation (e.g., an increase or a decrease) of any of the above in the animal can be a result of such a modulation in one or more organs in the animal. Weight loss of the animal can be, for example, a weight loss of about 1%, about 2%, about 3%, about 5%, about 6%, about 8%, about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, more than about 5%, more than about 10%, more than about 25%, or more than about 40%. 
     The term “exposed” or “exposure” means that the animal was subjected to an environment and/or an event that could result in being infected. Such exposures can be, but are not limited to, direct or indirect contact with or nearness to (e.g., sharing the same room, space, pen, instrument, furniture, food, or utensils) an infected person, accidental dissemination or release of biological agents (e.g., from a research laboratory, from a farm, from waste processing, from food processing), a bioterrorism event (e.g., from dissemination, deployment, release, or production of a biological agent), a civilian training event, a military training event, a battlefield event (e.g., from dissemination, deployment, release, or production of a biological agent), a medical procedure, a surgical procedure, or a health-related procedure. An exposed animal may or may not ultimately contract the infectious disease. An exposed animal may or may not have, in fact, come into direct contact or indirect contact with one or more contagions. Exposure can be through any means including but not limited to, contact with skin (e.g., broken skin or abraded skin), contact with blood or a bodily fluid (e.g., via an open sore or cut), injection, inhalation, ingestion, or contact with mucous membrane. In some instances a mucous membrane is a membrane that secretes mucin and that lines a bodily cavity and/or canal that lead to the outside of the body; examples include but are not limited to cavities and/or canals in the respiratory, digestive, and urogenital tracts, and these cavities and/or canals include but are not limited to the mouth, eyes, nose, eyelids, windpipe and lungs, stomach and intestines, and the ureters, urethra, and urinary bladder. “Post-exposure” means any time that is after exposure has occurred (e.g., any time from one microsecond to seconds, minutes, hours, days, weeks, months, or years after exposure). In some instances, administration post-exposure can be no more than about 1 minute, about 1 minute, about 5 minutes, about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 6 months, about 9 months, about 1 year, about 2 years, about 5 years, about 10 years or not less than about 10 years, after exposure. “Prior to exposure” means any time that is before exposure has occurred (e.g., any time from one microsecond to seconds, minutes, hours, days, weeks, or months, or years before exposure). In some instances, administration prior to exposure can be no more than about 1 hour, about 1 hour, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or not less than 2 months, before exposure. In some instances, the amount of time prior to exposure is informed by the half-life (i.e., the amount of time it takes for the animal&#39;s blood plasma concentration of the drug to decrease by half) of the drug (e.g., a COX-2 inhibitor, a COX-1 inhibitor, or an antibiotic) being administered; for example administration can be no more than about 1 half-life, about 1 half-life, about 2 half-lives, about 3 half-lives, about 4 half-lives, about 5 half-lives, about 6 half-lives, about 7 half-lives, about 8 half-lives, about 9 half-lives, about 10 half-lives, or about 20 half-lives of the drug, before exposure. 
     “Therapeutically effective amount” of a COX inhibitor means an amount effective to achieve a desired and/or beneficial effect. A therapeutically effective amount can be administered in one or more administrations. For some purposes of this invention, a therapeutically effective amount is an amount appropriate to treat an infectious disease. By treating an infectious disease is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any method known in the art, such as measurement of PGE-2 production, Arg2 expression, bacterial load, the level of relevant antigens in blood serum, or measuring animal (e.g., a human patient) life. In some instances, the therapeutically effective amount can depend on many factors, including but not limited to the species, age, weight, specifics of the bacterial infection, specifics of the animal&#39;s physiology (e.g., immune system or state of health), or combinations thereof. 
     “Therapeutically effective amount” of an antibiotic means an amount effective to achieve a desired and/or beneficial effect. A therapeutically effective amount can be administered in one or more administrations. For some purposes of this invention, a therapeutically effective amount is an amount appropriate to treat an infectious disease. By treating an infectious disease is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any method known in the art, such as measuring bacterial load, measuring body temperature, monitoring of the level of relevant antigens in blood serum, or measuring animal (e.g., a human patient) life. In some instances, the therapeutically effective amount can depend on many factors, including but not limited to the species, age, weight, specifics of the bacterial infection, specifics of the animal&#39;s physiology (e.g., immune system or state of health), or combinations thereof. 
     Some embodiments of the invention can include methods of treating an animal. In some embodiments, the animal is a mammal, for example, but not limited to, a human, rodent (e.g., mice or rats), horse, dog, cat, pig, cow, or goat. In some embodiments, the mammal is a human. In other embodiments, the animal is in need of treatment for a disease, condition, or disorder related to an infectious disease (e.g., a bacterial infectious disease). In certain embodiments, a human is in need of the treatment for a disease, condition, or disorder related to an infectious disease (e.g., a bacterial infectious disease). For example, an animal (e.g., a human) in need thereof can include but is not limited to an animal (e.g., human) that was exposed to a bacterial infectious disease, that could in the future be exposed to a bacterial infectious disease, that displays symptoms of a bacterial infectious disease, or that is diagnosed with a bacterial infectious disease. 
     In some embodiments of the methods of the invention, the treating of an animal may occur in any manner of administration (e.g., for a COX inhibitor or for an antibiotic), including, but not limited to oral treatment (e.g., via pill or liquid), inhalation, aerosol, intranasal treatment, topical administration, or injection. For example, injection may include, but is not limited to, intravenous, intraperitoneal, intramuscular, or subcutaneous injection. Administration by inhalation (e.g., for a COX inhibitor or for an antibiotic), in some instances, can be delivered using an aerosol spray in the form of solution, dry powder, or cream. The aerosol can use, for example, a pressurized pack or a nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch. In other embodiments (e.g., for a COX inhibitor or for an antibiotic), the manner of administration (e.g., for a COX inhibitor or for an antibiotic) does not include topical administration. In additional embodiments, the manner of administration (e.g., for a COX inhibitor or for an antibiotic) does not include topical administration to an eye (e.g., with eye drops, creams, or gels). In still other embodiments, the manner of administration (e.g., for a COX inhibitor or for an antibiotic) does not include topical administration to an eye, but may include treatment of the eye by systemic administration (e.g., by pill or inhalation). In still other embodiments, treatment (e.g., by a COX inhibitor or by an antibiotic) does not include treatment of the eye. 
     In certain embodiments the methods of treating an animal can include treatment with an amount of a COX inhibitor (e.g., a COX-1 inhibitor or a COX-2 inhibitor) that is effective to treat the disease that the animal has or is suspected of having, or to bring about a desired physiological effect. In some embodiments, the amount of a COX inhibitor (i.e., a COX inhibitor which is one of the one or more COX inhibitors) is administered at a concentration of about 0.05 to about 800 mg/kg body weight, about 0.05 to about 200 mg/kg body weight, about 0.2 to about 40 mg/kg body weight, about 0.5 to about 20 mg/kg body weight, about 0.01 mg/kg, about 0.02 mg/kg, about 0.05 mg/kg, about 0.08 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, about 10.0 mg/kg, about 12.0 mg/kg, about 14.0 mg/kg, about 16.0 mg/kg, about 18.0 mg/kg, about 20.0 mg/kg, about 25.0 mg/kg, about 30.0 mg/kg, about 40.0 mg/kg, about 50.0 mg/kg, about 60.0 mg/kg, about 70.0 mg/kg, about 80.0 mg/kg, about 90.0 mg/kg, about 100.0 mg/kg, about 125.0 mg/kg, about 150.0 mg/kg, about 175.0 mg/kg, about 200.0 mg/kg, about 300.0 mg/kg, about 400.0 mg/kg, about 600.0 mg/kg, or about 800.0 mg/kg. In regard to some conditions, the dosage can be about 15 mg/kg body weight, about 75 mg/kg body weight, or about 200 mg/kg body weight. In some embodiments, the amount of a COX inhibitor (i.e., a COX inhibitor which is one of the one or more COX inhibitors) is administered at an amount of from about 0.05 to about 50 g, from about 1 mg to about 10 g, from about 10 mg to about 1 g, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1 g, about 2 g, about 5 g, about 10 g, about 20 g, about 30 g, or about 50 g. For instance, one or more doses (e.g., 1, 2, 3, 4, or 5 doses) can be administered in a 24 hour period or at any suitable interval. The aforementioned administration amounts and dosages of a COX inhibitor are examples of therapeutically effective amounts of a COX inhibitor. 
     In certain embodiments, the dosage of a COX inhibitor can be higher compared to a dosage a COX inhibitor for long term usage (e.g., weeks, months, years, or for the rest of one&#39;s life). In some embodiments, the dosage can be higher than one or more long term usage dosages by at about 2 fold, at least about 5 fold, at least about 10 fold, about 1.5 fold, about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 20 fold, about 40 fold, about 50 fold, about 75 fold, about 100 fold, or more than about 100 fold. The term “fold” is meant to indicate a multiplicative factor; for example, a dosage that is 2 fold higher than a long term dosage of 325 mg is calculated by multiplying by 2 to yield a dosage of 650 mg (i.e., 2 times the long term dosage). Long term usage dosages of COX inhibitors include, for example, dosages of a COX inhibitor used for extended periods of time (e.g., weeks, months, years, or for the rest of one&#39;s life) to treat diseases that can indicate such long term usage dosage regimes such as, but not limited to osteoarthritis, rheumatoid arthritis, or an injury (e.g., a sports injury). The aforementioned dosages of a COX inhibitor are examples of therapeutically effective amounts of a COX inhibitor. 
     Table 1 shows some Cox-2 inhibitors and some examples of long term dosages. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Generic 
                   
                   
                 Human Dose 
                 Route of 
               
               
                 Name 
                 Brand Name 
                 Source 
                 Used 
                 Administration 
               
               
                   
               
             
            
               
                 Lumiracoxib 
                 Prexige 
                 Novartis 
                 50 mg, 100 mg, 
                 oral 
               
               
                   
                   
                   
                 and 400 mg 
                   
               
               
                 Etoricoxib 
                 Arcoxia 
                 Merck 
                   
                 oral 
               
               
                 Valdicoxib 
                 Bextra 
                 Pfizer 
                 40 mg tab 2× day 
                 oral 
               
               
                 Roficoxib 
                 Vioxx 
                 Pfizer 
                 12.5 mg, 25 mg, 
                 oral 
               
               
                   
                   
                   
                 50 mg tabs  
                   
               
               
                   
                   
                   
                 2× day 
                   
               
               
                 Etodolac 
                 Lodine 
                 Wyeth,  
                 200 mg, 300 mg, 
                 oral 
               
               
                   
                   
                 Possibly 
                 400 mg, 500 mg 
                   
               
               
                   
                   
                 Pfizer 
                 and 600 mg 
                   
               
               
                   
                   
                   
                 capsules 2× day 
                   
               
               
                 Celecoxib 
                 Celebrex 
                 Pfizer 
                 200 mg and  
                 oral 
               
               
                   
                   
                   
                 400 mg capsules  
                   
               
               
                   
                   
                   
                 2× day 
                   
               
               
                 Indomethacin 
                 Indocin 
                   
                 25 mg, 50 mg, 
                 oral 
               
               
                   
                   
                   
                 75 mg, 150 mg, 
                   
               
               
                   
                   
                   
                 200 mg 
               
               
                   
               
            
           
         
       
     
     It is possible to employ many concentrations and/or dosage regimes in the methods of the present invention. Adjusting and testing any number of concentrations and/or dosage regimes can be used in order to find one that achieves the desired result in a given circumstance. Moreover, some embodiments of the methods of the invention can include administration of one or more other therapeutic agents, including but not limited to antibiotics. In other embodiments, no antibiotics are administered. 
     In certain embodiments the methods of treating an animal can include treatment (e.g., in combination with one or more COX inhibitors) with an amount of an antibiotic (i.e., the antibiotic may be one of the one or more antibiotics) that is effective to treat the disease that the animal has, or is suspected of having, or to bring about a desired physiological effect. In some embodiments, the amount of an antibiotic is administered at a concentration of about 0.05 to about 200 mg/kg body weight, about 0.2 to about 40 mg/kg body weight, about 0.5 to about 20 mg/kg body weight, about 0.01 mg/kg, about 0.02 mg/kg, about 0.05 mg/kg, about 0.08 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, about 10.0 mg/kg, about 12.0 mg/kg, about 14.0 mg/kg, about 16.0 mg/kg, about 18.0 mg/kg, about 20.0 mg/kg, about 25.0 mg/kg, about 30.0 mg/kg, about 40.0 mg/kg, about 50.0 mg/kg, about 60.0 mg/kg, about 70.0 mg/kg, about 80.0 mg/kg, about 90.0 mg/kg, about 100.0 mg/kg, about 125.0 mg/kg, about 150.0 mg/kg, about 175.0 mg/kg, about 200.0 mg/kg, about 300.0 mg/kg, or about 400.0 mg/kg. In regard to some conditions, the dosage can be about 15 mg/kg, about 25 mg/kg, or about 60 mg/kg body weight. In some embodiments, the amount of an antibiotic is administered at an amount of from about 0.1 mg to about 10 g, from about 1 mg to about 5 g, from about 10 mg to about 1 g, about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 8 g, or about 10 g. For instance, one or more doses (e.g., 1, 2, 3, 4, or 5 doses) can be administered in a 24 hour period or at any suitable interval. It is possible to employ many concentrations and/or dosage regimes in the methods of the present invention. Adjusting and testing any number of concentrations and/or dosage regimes can be used in order to find one that achieves the desired result in a given circumstance. In some embodiments, an antibiotics can be administered within about zero minutes, within about 5 minutes, within about 10 minutes, within about 20 minutes, within about 30 minutes, within about 60 minutes, within about 90 minutes, within about 120 minutes, within about 3 hours, within about 4 hours, within about 5 hours, within about 10 hours, within about 15 hours, within about 24 hours, within about 36 hours, within about 48 hours, within about 50 hours, within about 3 days, within about 4 days, within about 5 days, within about 1 week, or within about 2 weeks of one or more of the administrations of a Cox inhibitor. Moreover, some embodiments of the methods of the invention can include administration of one or more additional therapeutic agents, at any timing specified herein for a COX inhibitor or for an antibiotic. The aforementioned are examples of therapeutically effective amounts of an antibiotic. 
     EXAMPLE SET A 
     Example A1 —Burkholderia thailandensis  (Bt) and Bps Induce PGE-2 Production in a Time and Dose-Dependent Manner 
       Burkholderia pseudomallei  can induce cell death known as pyroptosis in macrophages as early as eight hours post infection at a multiplicity of infection (MOI) of 10:1 or greater. In pilot experiments, J774 macrophages infected with Bt at MOI 10:1 or 1:1 displayed 80% and 28% cytotoxicity, respectively at eight hours post-infection. Therefore, experiments utilizing primary BMDM or macrophage cell lines were limited to an eight hour experimental time course using  Burkholderia  at MOI 1:1 or lower (1:10). 
     In order to elucidate innate immune responses to  Burkholderia  infection, a TLR PCR array was performed on J774A-1 macrophages infected with Bt. Consistent with previous reports, Bt upregulated expression of TLR1 and TLR2 by two hours post-infection, and increases in TLR1, TLR2, TLR3, TLR4, and TLR5 mRNA expression were observed by eight hours post-infection, as shown in  FIG. 1A . No change in mRNA expression was observed for TLR6, TLR7, TLR8, or TLR9. Cox-2 mRNA expression increased more than 10,000 fold by eight hours post-infection with Bt, as shown in  FIG. 1B . 
     To confirm the PCR array, macrophages were infected with Bt and Bps, and supernatants were harvested for measurement of PGE-2 concentration. At four and eight hours post-infection, the levels of PGE-2 were increased in macrophages infected with Bt at MOI 1:1 compared to macrophages infected with Bt at MOI 1:10 and uninfected cells, as shown in  FIG. 2A . 
     Upon infection of BMDM with Bps, PGE-2 levels were also increased at four and six hours post-infection, as shown in  FIG. 2B . In addition, human lung alveolar epithelial cells (A549) produced high levels of PGE-2 in response to Bt after eight and 24 hours of infection, as shown in  FIG. 2C , indicating that the response is not restricted to the mouse macrophage. 
     Example A2—Endogenous PGE-2 Enhances Intracellular Survival of Bt and Bp 
     The influence of PGE-2 on  Burkholderia  intracellular survival was assessed. J774A-1 macrophages pre-treated with NS398 (a selective Cox-2 inhibitor) demonstrated enhanced intracellular killing of Bt, as evidenced by a decrease in survival of intracellular bacteria compared to non-treated cells six hours post-infection, shown in  FIG. 3A . 
     To verify that endogenous PGE-2 is responsible for the suppression of bacterial killing, PGE-2 levels were measured in the supernatants of NS398-treated and non-treated macrophages. PGE-2 levels were reduced in cells treated with NS398, as shown in  FIG. 3B . Similar to that observed with Bt, pre-treatment of BMDM with NS398 led to a reduction in Bps survival six hours post-invasion, as shown in  FIG. 3C . The suppression of Bps growth by NS398 was abrogated when 1 μM of exogenous PGE-2 was added to the Cox-2 inhibitor pre-treated cells, also shown in  FIG. 3C . These results demonstrate a decline in  Burkholderia&#39;s  intracellular survival after inhibiting endogenous PGE-2 production. 
     Example A3—PGE-2 Suppresses Nitric Oxide Generation and Induces Arginase Expression 
     PGE-2 has been shown to suppress NO levels. Therefore, the downstream effect of PGE-2 on NO in response to Bt and Bps infection was evaluated. NO was determined using the Griess assay which measures nitrite, the stable end product of NO. A statistically significant increase in NO levels were observed in BMDM infected with Bt and Bps by four and six hours post-infection, respectively, as shown in  FIGS. 4A and 4B . Pre-treatment of macrophages with the Cox-2 inhibitor NS398 resulted in higher production of NO, while the addition of 1 μM PGE-2 to NS398-treated macrophages reduced NO levels, also shown in  FIGS. 4A and 4B . This indicates that PGE-2 is suppressing NO production in macrophages infected with Bps or Bt. 
     The effect of endogenous PGE-2 production on the expression of iNOS, which is required for the synthesis of NO, was examined. A two-fold increase in iNOS expression in Bt infected cells after treatment with NS398 was observed, as shown in  FIG. 4B . However, no differences in iNOS mRNA expression in NS398-treated or PGE-2-treated cells infected with Bps were observed (data not shown). 
     Since arginase competes with iNOS for L-arginine, PGE-2 induction of arginase could alter the level of NO production during  Burkholderia  infection. Arg1 expression was not detected after four hours of infection, but the expression of Arg2 was increased in Bt-infected BMDM. This was confirmed in Bps-infected BMDM, which demonstrated a 155-fold increase in Arg2 expression after four hours. NS398 pre-treated macrophages demonstrated a reduction in Arg2 expression, while treatment with exogenous PGE-2 led to a 376-fold increase in Arg2 expression, as shown in  FIG. 4C . These data suggest that endogenous PGE-2 may interfere with NO production by enhancing Arg2 expression. 
     Example A4—Arginase Enhances  Burkholderia intracellular  Survival 
     Many intracellular pathogens induce arginase expression as a mechanism for suppressing intracellular killing by macrophages. To determine whether Arg2 directly interferes with NO production and enhances  Burkholderia&#39;s  intracellular survival, the NO levels (determined using the Griess assay) and intracellular bacterial survival were examined after inhibition of arginase with nor-NOHA. A decrease in both Bt and Bps intracellular survival was observed six hours post-infection in nor-NOHA treated cells, as shown in  FIGS. 5A and 5B . Furthermore, nor-NOHA treatment led to a increase in NO levels four hours post-infection, as shown in  FIGS. 5C and 5D . This indicates that arginase is promoting bacterial survival, which might be partly attributed to its impact on NO production. 
     Example A5—PGE-2 is Produced in the Lung During  Burkholderia  Infection 
     Pneumonia is a frequent clinical presentation of melioidosis and is involved in at least half of all melioidosis cases. Patients presenting with pneumonia are more prone to septic shock compared with other clinical primary presentations. To study the role of PGE-2 in pulmonary melioidosis, BALB/c mice (Bps susceptible strain) were challenged by the intranasal route with a lethal dose of Bt (10 6  cfu) or Bps (3×10 3  cfu). PGE-2 levels were measured in lung homogenates obtained at 24, 48, and 72 hours post-infection. An increase in PGE-2 was observed after 72 hours of infection, as shown in  FIGS. 6 and 7 . 
     Example A6—Arg2 Expression Increases in Bt Challenged Mice and Decreases after Blocking PGE-2 Production 
     PGE-2 enhanced Arg2 expression and bacterial intracellular survival in vitro. Therefore, Arg2 expression was evaluated in the lungs of Bt-infected mice. A six to eight fold increase in Arg2 expression was observed at 48 and 72 hours post-infection, as shown in  FIG. 8 , while no increase in iNOS expression was observed up to 72 hours. Western blot analysis of lung and liver tissue for Arg2 demonstrated a reduction in Arg2 in the lungs, but not in the liver, of Celecoxib-treated mice compared to mock-treated mice 48 hours after pulmonary Bt infection, as shown in  FIG. 9 . Similarly, immunohistochemical staining analyses revealed a reduction in the number of Arg2 positively-stained cells in Celecoxib-treated mice, shown in  FIG. 10 . Both Western blot and IHC staining demonstrated increased Arg2 in the lungs of Bt-infected mice compared to uninfected mice. 
     To further confirm differences in Arg2 expression in the lungs of Celecoxib- and mock-treated mice, a quantitative assay for urea was employed. Urea is a byproduct of L-arginine degradation by arginase and thus provides an indirect measurement of Arg activity. Urea levels were lower in the lungs of Celecoxib-treated mice compared to mock-treated animals, as shown in  FIG. 11 . Taken together, these findings support that Cox-2 inhibition resulted in a reduction in Arg2 activity in the lungs of infected mice. 
     Example A7—Celecoxib Treatment Reduces Lung Inflammation During  Burkholderia  Infection 
     Similar to the histological findings, high concentrations of IL-1α and IL-6 (pro-inflammatory cytokines) and KC (neutrophil chemokine) were measured in the lungs of mock-treated mice 48 hours post-infection with Bt. Conversely, IL-1α, IL-6 and KC were reduced in the lungs of Celecoxib-treated mice, as shown in  FIG. 12 . Overall, these data suggest that Celecoxib-treated mice have a reduction in lung inflammation during the early course of Bt infection. 
     EXAMPLE SET B 
     Method—Mice and Bacterial Challenges 
     Animal experiments were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Tulane University Institutional Animal Care and Use Committee. Six to eight week old, female BALB/c mice (Charles River) were maintained under pathogen-free conditions and fed sterile food and water ad libitum. Infections utilizing Bps were performed under Animal Biosafety Level 3 containment. 
       Burkholderia pseudomallei  strain 1026b (BEI Resources) was used in this study. For infectious challenge, mice were anesthetized with Ketamine/xylazine (88 mg/kg) (Fort Dodge Animal Health). The bacterial inoculum contained 3×10 3  cfu (˜4 LD 50 ) suspended in 40 μl sterile saline and 20 μL was delivered to each nostril via pipet. Bacterial cfu were confirmed by plating the inoculum on LB agar. Euthanasia endpoints used in this study included loss of &gt;20% body weight, hunched posture and decreased movement or response to stimuli, or paralysis. In a subset of experiments, mice were treated with the selective COX-2 inhibitor, (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide) (NS398) (Cayman Chemicals), 3 hours post-exposure. Mice received 50 μl of NS398 (15 mg/kg) dissolved in DMSO or vehicle control (DMSO) by intraperitoneal injection. Treatments were repeated for two consecutive days. After euthanasia, tissues were removed, weighed and homogenized in 1 ml 0.9% sterile saline. Serial dilutions of tissue homogenates were plated on LB agar and bacterial cfu were counted after 2-4 days of incubation at 37° C. 
     Method—Cell Culture and In Vitro Experiments 
     J774A.1 murine macrophage-like cells were obtained from ATCC. Cells were propagated in media containing DMEM (Invitrogen) with 10% FBS (Atlanta Biologicals), 1% Pen/Strep (Invitrogen) and 1% sodium bicarbonate (Invitrogen). Bone marrow-derived macrophages (BMDM) were extracted from 8-10 week old BALB/c mice as previously described (WEISCHENFELDT et al., “Bone Marrow-Derived Macrophages: Isolation and Applications” (2008) Cold Spring Harb. Protoc., Vol. 3, Issue 12, doi:10.1101/pdb.prot5080). BMDM were propagated in RPMI (ATCC), containing 15% L929 fibroblast-conditioned media, 2 g/L D-glucose (Invitrogen), 10% FBS, 5% horse serum (Invitrogen), 1% Pen/Strep and 2 mM L-glutamine (Invitrogen). Prior to each experiment, the cytotoxic dose of bacteria and chemical treatments were pre-determined using a colorimetric assay for LDH release (Clontech). Intracellular survival assays were performed as previously described in Burtnick et al. 2008 (BURTNICK et al., “ Burkholderia pseudomallei  type III secretion system mutants exhibit delayed vacuolar escape phenotypes in RAW 264.7 murine macrophages” Infect Immun (2008) Vol. 76, pp. 2991-3000). In some experiments, cells were treated with 100 μM of NS398, 100 μM nor-N ω -hydroxy-L-arginine (nor-NOHA; Cayman Chemical), or 1 μM PGE-2 (Sigma). PGE-2 was measured in cell culture supernatants and lung homogenates by competitive ELISA (Pierce). Nitric oxide was measured as its stable end product nitrite by Griess assay (Invitrogen). 
     Method—TLR Pathway PCR Array 
     Fold-change in mRNA expression of 84 genes central to TLR-mediated signal transduction and innate immunity were measured by PCR array following the manufacturer&#39;s protocol and data analysis software (SABiosciences). 
     Method—Real Time-PCR 
     RT-PCR was conducted using an iCycler (BioRad) with iScript cDNA Synthesis Kit (BioRad). 1 μg of RNA was converted to cDNA following the manufacturer&#39;s protocol. 1 μl of cDNA was added to 12.5 μL of iQ SYBR Green Super Mix containing 350 nM of each forward and reverse primer. Primer sequences were as follows: 
     
       
         
           
               
               
            
               
                   
                 GAPDH: 
               
               
                   
                 forward, 
               
               
                   
                 (SEQ ID NO: 1) 
               
               
                   
                 5′-ACAGCCGCATCTTCTTGTGCAGTG-3′; 
               
               
                   
                   
               
               
                   
                 reverse, 
               
               
                   
                 (SEQ ID NO: 2)  
               
               
                   
                 5′-GGCCTTGACTGTGCCGTTGAATTT-3′; 
               
               
                   
                   
               
               
                   
                 Arg1: 
               
               
                   
                 forward, 
               
               
                   
                 (SEQ ID NO: 3) 
               
               
                   
                 5′-GGGCTGGACCCAGCATTCACCCCG-3′; 
               
               
                   
                   
               
               
                   
                 reverse, 
               
               
                   
                 (SEQ ID NO: 4) 
               
               
                   
                 5′TCACTTAGGTGGTTTAAGGTAGTC-3′; 
               
               
                   
                   
               
               
                   
                 Arg2: 
               
               
                   
                 forward, 
               
               
                   
                 (SEQ ID NO: 5) 
               
               
                   
                 5′-GACCCTAAACTGGCTCCAGCCACA-3′; 
               
               
                   
                   
               
               
                   
                 reverse, 
               
               
                   
                 (SEQ ID NO: 6) 
               
               
                   
                 5′-CTAAATTCTCACACATTCTTCATT-3′; 
               
               
                   
                   
               
               
                   
                 iNOS: 
               
               
                   
                 forward, 
               
               
                   
                 (SEQ ID NO: 7) 
               
               
                   
                 5′-ATGACCAGTATAAGGCAAGC-3′; 
               
               
                   
                   
               
               
                   
                 reverse, 
               
               
                   
                 (SEQ ID NO: 8) 
               
               
                   
                 5′-GCTCTGGATGAGCCTATATTG-3′; 
               
               
                   
                   
               
               
                   
                 COX-2: 
               
               
                   
                 forward, 
               
               
                   
                 (SEQ ID NO: 9) 
               
               
                   
                 5′-GGAGAGAAGGAAATGGCTGCA-3′; 
               
               
                   
                   
               
               
                   
                 reverse, 
               
               
                   
                 (SEQ ID NO: 10) 
               
               
                   
                 5′-ATCTAGTCTGGAGTGGGAGG-3′. 
               
            
           
         
       
     
     Nuclease-free water was added to bring the total reaction volume to 25 μL. PCR was performed using the following conditions: reverse transcriptase inactivation (95° C., 3 min) followed by 40 PCR cycles (95° C., 15 seconds and 60° C., 30 seconds) followed by melt curve analysis. Fold change (up- or down-regulation) relative to base line expression in uninfected cells was calculated using the ΔΔCt method using Ct values for arginase 1, arginase 2, iNOS, COX-2, and GAPDH. 
     Method—Detection of COX-2 and Arginase 
     For Western blot, equal amounts of protein (50 μg) from cell lysates or lung homogenates were resolved by SDS-PAGE and transferred to nitrocellulose using an iBLOT (Invitrogen). Detection of COX-2 enzyme was performed using a 1:1000 dilution of rabbit polyclonal anti-COX-2 (Cell Signaling Technology), followed by peroxidase-conjugated, donkey anti-rabbit IgG (1:5000). Arg2 was detected using a 1:200 dilution of rabbit polyclonal anti-mouse Arg2 (sc-20151, Santa Cruz) and Arg1 was detected using a 1:500 dilution of Arg1 antibody 18351 (Santa Cruz). Mouse Arg2-transfected 293T cell lysate (Santa Cruz) was used a positive control for Arg2 and 5 μg of mouse liver extract was used a positive control for Arg1. β-actin, a protein loading control, was detected using 1:1000 dilution of polyclonal rabbit anti-mouse β-actin (Cell Signaling). Detection of bound antibodies was visualized by a chromogenic reaction using Opti-4CN Substrate (BioRad). 
     Method—Statistical Analysis 
     Statistical analyses were performed using Prism 5.0 software (Graph Pad). Kaplan-Meier survival curves were compared by log-rank analysis. All other data were analyzed using a one-way or two-way ANOVA followed by the Bonferroni post-test to determine statistical differences between groups. p&lt;0.05 was considered statistically significant. All data are representative of at least two independent experiments. 
     Example B1 —B. pseudomallei  Rapidly Induces PGE-2 Production by Macrophages 
     In order to identify host cell signaling pathways that might contribute to  B. pseudomallei  intracellular persistence, we performed a Toll-like receptor (TLR or Tlr) PCR array on J744A.1 macrophages infected with  B. thailandensis. B. thailandensis  is a commonly used biosafety level 2 surrogate organism for the study of  B. pseudomallei  and, with the exception of capsular polysaccharide, possesses all of the known  B. pseudomallei  virulence determinants such as Type 3 and Type 6 secretion systemS. Although  B. thailandensis  is 1,000- to 100,000-fold less virulent than  B. pseudomallei  in animal models, the organisms behave very similarly in vitro.  B. thailandensis  and  B. pseudomallei  induce pyroptosis in macrophages as early as 8 hours post infection at a multiplicity of infection (MOI) 10 or greater. In pilot experiments, we determined that J774A.1 macrophages infected with  B. thailandensis  at MOI 10 or 1 displayed 80% and 28% cytotoxicity, respectively at 8 hours post-infection (data not shown). Therefore, experiments utilizing J774A.1 macrophages or primary bone marrow-derived macrophages (BMDM) were limited to an eight hour experimental time course using  B. thailandensis  or  B. pseudomallei  at MOI 1 or lower (0.1). 
     Table 2 shows the fold-change in mRNA expression of 84 different genes from the Toll-like receptor pathway. J774A.1 macrophages were infected with  B. thailandensis  E264 (MOI 1) and gene expression was analyzed at 2 and 8 hours post-infection. Change in mRNA expression is represented as fold change over uninfected controls. The abbreviation n.c. indicates no change in expression. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                 Fold- 
                 Fold- 
               
               
                   
                   
                 Difference 
                 Difference 
               
               
                 Symbol 
                 Description 
                 2 h 
                 8 h 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 Agfg1 
                 ArfGAP with FG repeats 1 
                 n.c. 
                 128.0 
               
               
                 Btk 
                 Bruton agammaglobulinemia tyrosine kinase 
                 n.c. 
                 n.c. 
               
               
                 Casp8 
                 Caspase 8 
                 n.c. 
                 n.c. 
               
               
                 Ccl2 
                 Chemokine (C-C motif) ligand 2 
                 5.0 
                 13.9 
               
               
                 Cd14 
                 CD14 antigen 
                 n.c. 
                 4.5 
               
               
                 Cd80 
                 CD80 antigen 
                 n.c. 
                 17.1 
               
               
                 Cd86 
                 CD86 antigen 
                 n.c. 
                 3821.7 
               
               
                 Cebpb 
                 CCAAT/enhancer binding protein (C/EBP), beta 
                 n.c. 
                 24.2 
               
               
                 Chuk 
                 Conserved helix-loop-helix ubiquitous kinase 
                 −5.4 
                 1448.1 
               
               
                 Clec4e 
                 C-type lectin domain family 4, member e 
                 n.c. 
                 274.3 
               
               
                 Csf2 
                 Colony stimulating factor 2 (granulocyte-macrophage) 
                 4.4 
                 24.2 
               
               
                 Csf3 
                 Colony stimulating factor 3 (granulocyte) 
                 66.2 
                 5042.7 
               
               
                 Cxcl10 
                 Chemokine (C-X-C motif) ligand 10 
                 30.9 
                 8.0 
               
               
                 Eif2ak2 
                 Eukaryotic translation initiation factor 2-alpha kinase 2 
                 7.2 
                 445.7 
               
               
                 Elk1 
                 ELK1, member of ETS oncogene family 
                 n.c. 
                 5.2 
               
               
                 Fadd 
                 Fas (TNFRSF6)-associated via death domain 
                 n.c. 
                 n.c. 
               
               
                 Fos 
                 FBJ osteosarcoma oncogene 
                 n.c. 
                 34.2 
               
               
                 Hmgb1 
                 High mobility group box 1 
                 −5.8 
                 n.c. 
               
               
                 Hras1 
                 Harvey rat sarcoma virus oncogene 1 
                 n.c. 
                 n.c. 
               
               
                 Hspa1a 
                 Heat shock protein 1A 
                 n.c. 
                 n.c. 
               
               
                 Hspd1 
                 Heat shock protein 1 (chaperonin) 
                 n.c. 
                 7643.4 
               
               
                 Ifnb1 
                 Interferon beta 1, fibroblast 
                 5.8 
                 8.0 
               
               
                 Ifng 
                 Interferon gamma 
                 n.c. 
                 8.0 
               
               
                 Ikbkb 
                 Inhibitor of kappaB kinase beta 
                 n.c. 
                 55.7 
               
               
                 Il10 
                 Interleukin 10 
                 10.1 
                 97.0 
               
               
                 Il12a 
                 Interleukin 12A 
                 n.c. 
                 8.0 
               
               
                 Il1a 
                 Interleukin 1 alpha 
                 21.8 
                 103.9 
               
               
                 Il1b 
                 Interleukin 1 beta 
                 26.9 
                 194.0 
               
               
                 Il1r1 
                 Interleukin 1 receptor, type I 
                 n.c. 
                 n.c. 
               
               
                 Il2 
                 Interleukin 2 
                 n.c. 
                 n.c. 
               
               
                 Il6 
                 Interleukin 6 
                 76.1 
                 891.4 
               
               
                 Il6ra 
                 Interleukin 6 receptor, alpha 
                 n.c. 
                 n.c. 
               
               
                 Irak1 
                 Interleukin-1 receptor-associated kinase 1 
                 −5.0 
                 73.5 
               
               
                 Irak2 
                 Interleukin-1 receptor-associated kinase 2 
                 n.c. 
                 2702.3 
               
               
                 Irf1 
                 Interferon regulatory factor 1 
                 n.c. 
                 207.9 
               
               
                 Irf3 
                 Interferon regulatory factor 3 
                 n.c. 
                 25.9 
               
               
                 Jun 
                 Jun oncogene 
                 n.c. 
                 1552.0 
               
               
                 Lta 
                 Lymphotoxin A 
                 n.c. 
                 n.c. 
               
               
                 Ly86 
                 Lymphocyte antigen 86 
                 −13.4 
                 n.c. 
               
               
                 Ly96 
                 Lymphocyte antigen 96 
                 n.c. 
                 n.c. 
               
               
                 Map2k3 
                 Mitogen-activated protein kinase kinase 3 
                 n.c. 
                 n.c. 
               
               
                 Map2k4 
                 Mitogen-activated protein kinase kinase 4 
                 n.c. 
                 36.7 
               
               
                 Map3k1 
                 Mitogen-activated protein kinase kinase kinase 1 
                 n.c. 
                 8.0 
               
               
                 Map3k7 
                 Mitogen-activated protein kinase kinase kinase 7 
                 n.c. 
                 831.7 
               
               
                 Mapk8 
                 Mitogen-activated protein kinase 8 
                 n.c. 
                 128 
               
               
                 Mapk8ip3 
                 Mitogen-activated protein kinase 8 interacting protein 3 
                 n.c. 
                 1024 
               
               
                 Mapk9 
                 Mitogen-activated protein kinase 9 
                 n.c. 
                 55.7 
               
               
                 Muc13 
                 Mucin 13, epithelial transmembrane 
                 −8.2 
                 8 
               
               
                 Myd88 
                 Myeloid differentiation primary response gene 88 
                 n.c. 
                 18.3 
               
               
                 Nfkb1 
                 Nuclear factor of kappa light polypeptide gene enhancer 
                 8.8 
                 n.c. 
               
               
                   
                 in B-cells 1, p105 
                   
                   
               
               
                 Nfkb2 
                 Nuclear factor of kappa light polypeptide gene enhancer  
                 n.c. 
                 8 
               
               
                   
                 in B-cells 2, p49/p100 
                   
                   
               
               
                 Nfkbia 
                 Nuclear factor of kappa light polypeptide gene enhancer  
                 6.2 
                 19.6 
               
               
                   
                 in B-cells inhibitor, alpha 
                   
                   
               
               
                 Nfkbib 
                 Nuclear factor of kappa light polypeptide gene enhancer  
                 n.c. 
                 8 
               
               
                   
                 in B-cells inhibitor, beta 
                   
                   
               
               
                 Nfkbil1 
                 Nuclear factor of kappa light polypeptide gene enhancer  
                 n.c. 
                 n.c. 
               
               
                   
                 in B-cells inhibitor-like 1 
                   
                   
               
               
                 Nfrkb 
                 Nuclear factor related to kappa B binding protein 
                 n.c. 
                 18.3 
               
               
                 Nr2c2 
                 Nuclear receptor subfamily 2, group C, member 2 
                 n.c. 
                 5.6 
               
               
                 Peli1 
                 Pellino 1 
                 n.c. 
                 3326.9 
               
               
                 Pglyrp1 
                 Peptidoglycan recognition protein 1 
                 n.c. 
                 8 
               
               
                 Ppara 
                 Peroxisome proliferator activated receptor alpha 
                 n.c. 
                 22.6 
               
               
                 Ptgs2 
                 Prostaglandin-endoperoxide synthase 2 
                 430.5 
                 16384 
               
               
                 (COX-2) 
                   
                   
                   
               
               
                 Rel 
                 Reticuloendotheliosis oncogene 
                 8.2 
                 n.c. 
               
               
                 Rela 
                 V-rel reticuloendotheliosis viral oncogene homolog A 
                 n.c. 
                 n.c. 
               
               
                   
                 (avian) 
                   
                   
               
               
                 Ripk2 
                 Receptor (TNFRSF)-interacting serine-threonine kinase 2 
                 n.c. 
                 6.4 
               
               
                 Tbk1 
                 TANK-binding kinase 1 
                 n.c. 
                 n.c. 
               
               
                 Ticam1 
                 Toll-like receptor adaptor molecule 1 
                 n.c. 
                 n.c. 
               
               
                 Ticam2 
                 Toll-like receptor adaptor molecule 2 
                 n.c. 
                 16 
               
               
                 Tirap 
                 Toll-interleukin 1 receptor (TIR) domain-containing  
                 6.7 
                 5.6 
               
               
                   
                 adaptor protein 
                   
                   
               
               
                 Tlr1 
                 Toll-like receptor 1 
                 n.c. 
                 84.4 
               
               
                 Tlr2 
                 Toll-like receptor 2 
                 n.c. 
                 2194.9 
               
               
                 Tlr3 
                 Toll-like receptor 3 
                 n.c. 
                 42.2 
               
               
                 Tlr4 
                 Toll-like receptor 4 
                 5.8 
                 207.9 
               
               
                 Tlr5 
                 Toll-like receptor 5 
                 n.c. 
                 7.4 
               
               
                 Tlr6 
                 Toll-like receptor 6 
                 n.c. 
                 n.c. 
               
               
                 Tlr7 
                 Toll-like receptor 7 
                 n.c. 
                 −4.5 
               
               
                 Tlr8 
                 Toll-like receptor 8 
                 n.c. 
                 −8 
               
               
                 Tlr9 
                 Toll-like receptor 9 
                 n.c. 
                 −6.4 
               
               
                 Tnf 
                 Tumor necrosis factor 
                 7.2 
                 7.4 
               
               
                 Tnfaip3 
                 Tumor necrosis factor, alpha-induced protein 3 
                 5.8 
                 42.2 
               
               
                 Tnfrsf1a  
                 Tumor necrosis factor receptor superfamily, member 1a 
                 76.1 
                 n.c. 
               
               
                 Tollip 
                 Toll interacting protein 
                 n.c. 
                 9.1 
               
               
                 Tradd 
                 TNFRSF1A-associated via death domain 
                 n.c. 
                 181.0 
               
               
                 Traf6 
                 Tnf receptor-associated factor 6 
                 28.8 
                 588.1 
               
               
                 Ube2n 
                 Ubiquitin-conjugating enzyme E2N 
                 10.9 
                 32 
               
               
                 Ube2v1 
                 Ubiquitin-conjugating enzyme E2 variant 1 
                 n.c. 
                 256 
               
               
                   
               
            
           
         
       
     
       B. thailandensis  upregulated expression of TLR1 and TLR2 by two hours post-infection, and increases in TLR1, TLR2, TLR3, TLR4, and TLR5 mRNA expression were observed by eight hours post-infection (Table 2). No change in mRNA expression was observed for TLR6, TLR7, TLR8, or TLR9. An increase (430-fold) in COX-2 mRNA expression occurred by two hours post-infection and further increased by &gt;16,000-fold at eight hours (Table 2). COX-2 is an enzyme involved in the production of PGE-2. 
     To confirm the TLR array results obtained for  B. thailandensis -infected J774A.1 macrophages, BMDM were infected with  B. thailandensis and B. pseudomallei  (MOI 1) and COX-2 mRNA expression was measured by RT-PCR.  B. thailandensis  and  B. pseudomallei  both up-regulated COX-2 mRNA expression in BMDM to a similar extent ( FIG. 13A ), although the levels of mRNA expression were lower than that observed for  B. thailandensis -infected J774A.1 cells and may reflect differences between immortalized and primary cell lines ( FIG. 13A , Table 2). COX-2 enzyme and its end product, PGE-2, were also produced by macrophages in response to  B. pseudomallei  in a time- and dose-dependent manner ( FIG. 13B-C ). Since lipopolysaccharide (LPS) of Gram-negative bacteria is known to induce COX-2 and PGE-2 production, we evaluated whether the PGE-2 response of infected macrophages was simply a passive signaling event mediated by TLR4 recognition of LPS. Notably, heat inactivation of  B. pseudomallei  appeared to abolished COX-2 and PGE-2 expression ( FIG. 13A-C ) indicating that viable bacteria and/or bacterial proteins are required for early PGE-2 production by macrophages. 
     Example B2—PGE-2 Enhances  B. pseudomallei  Intracellular Survival 
     Because PGE-2 has been shown to suppress macrophage bactericidal mechanisms, we assessed the impact of COX-2 activation and PGE-2 production on  B. pseudomallei  intracellular survival using the selective COX-2 inhibitor, NS398. Preliminary dose-response experiments were conducted using 10 to 200 μM NS398 (data not shown). BMDM treated with &gt;100 μM NS398 demonstrated enhanced intracellular killing of  B. pseudomallei  compared to non-treated cells by six hours post-infection ( FIG. 14A ). To verify the specificity of NS398 and that endogenous PGE-2 is responsible for the suppression of bacterial killing, exogenous PGE-2 was added to NS398-treated cells. Addition of PGE-2 to the cell cultures restored  B. pseudomallei  intracellular survival ( FIG. 14A ) confirming that PGE-2 promotes a favorable environment for  B. pseudomallei.    
     We evaluated the downstream effect of PGE-2 on the macrophage NO response to  B. pseudomallei  infection. Treatment of BMDM with the COX-2 inhibitor NS398 led to an increase in nitrite, the stable end product of NO ( FIG. 14B ). This effect was not drug-specific because similar results were obtained using the COX inhibitor, indomethacin (data not shown). Conversely, the addition of exogenous PGE-2 to NS398-treated macrophages reduced nitrite levels in  B. pseudomallei -infected cells ( FIG. 14B ). This suggests that PGE-2-mediated suppression of NO production may partially contribute to  B. pseudomallei  intracellular survival. 
     Example B3—Arginase 2 Enhances Bps Intracellular Survival 
     We next examined the effect of endogenous PGE-2 production on the expression of iNOS, which is required for the synthesis of NO. We did not observe any apparent change in iNOS mRNA expression in NS398- or PGE-2-treated cells compared to controls infected with  B. pseudomallei  ( FIG. 15A ). This suggested that PGE-2 did not directly regulate iNOS in  B. pseudomallei -infected cells and that other mechanisms were responsible for the reduced levels of NO. 
     Since the enzymes arginase 1 (Arg1) and 2 (Arg2) compete with iNOS for the substrate, L-arginine, we postulated that PGE-2 induction of arginase could alter the level of NO production during  B. pseudomallei  infection. PGE-2 induction of macrophage arginase promotes tumor cell growth by suppressing NO-mediated tumor cytotoxicity. Arg1 expression was not detected after four hours of  B. pseudomallei -infection, but the expression of Arg2 was increased (155-fold) in  B. pseudomallei -infected BMDM ( FIG. 15A ). NS398-treated macrophages demonstrated a reduction in Arg2 expression while treatment with exogenous PGE-2 increased Arg2 expression by 376-fold ( FIG. 15A ). These data suggest that endogenous PGE-2 may interfere with NO production by enhancing Arg2 expression. 
     Modulation of the arginase pathway contributes to the intracellular survival of multiple pathogens, including  Salmonella  and  Mycobacterium  spp. To determine whether Arg2 directly interferes with NO production and enhances  B. pseudomallei  intracellular survival, we treated macrophages with the arginase inhibitor, nor-NOHA. A decrease in  B. pseudomallei  intracellular survival was observed in nor-NOHA-treated BMDM ( FIG. 15B ) and this corresponded to an increase in nitrite levels ( FIG. 15C ). Collectively, these results indicate that Arg2 expression promotes  B. pseudomallei  intracellular survival, in part, through suppression of macrophage NO synthesis. 
     Example B4—PGE-2 is Produced During Bps Pulmonary Infection 
     Inhalational infection with  B. pseudomallei  is a natural route of exposure and represents a route of infection in a deliberate biological attack. In order to evaluate the role of PGE-2 during pneumonic melioidosis, genetically-susceptible BALB/c mice were challenged by the intranasal route with a lethal dose of  B. pseudomallei  (3×10 3  cfu). Pulmonary infection with  B. pseudomallei  progressed rapidly in mice leading to greater than 20% weight loss by 72 hours post-infection ( FIG. 16 ). An increase in lung PGE-2 was observed by 72 hours post-infection and correlated with disease progression (p=0.029 by Pearson statistical analysis) ( FIG. 16 ). These results indicate that PGE-2 may play an important role in pneumonic melioidosis during the early stages of infection. 
     Example B5—Protective Efficacy of COX-2 Inhibition Against Pneumonic Melioidosis 
     Because PGE-2 inhibition enhanced bacterial clearance in vitro and because PGE-2 is elevated in  B. pseudomallei -infected lungs, we evaluated the efficacy of COX-2 inhibition as a post-exposure therapeutic strategy against lethal  B. pseudomallei  pulmonary challenge. Mice were given NS398 or mock control by i.p. administration three hours after  B. pseudomallei  intranasal infection, and treatments were repeated for two consecutive days. Initiation of therapy within three hours is clinically relevant in the case of a known biological exposure to  B. pseudomallei , such as a laboratory accident. A daily maximum dose of 15 mg/kg of NS398 was selected based upon previously documented pharmacological efficacy in mice (particularly in reducing lung PGE-2) without any associated toxicity. Mock-treated mice infected with  B. pseudomallei  rapidly displayed signs of pulmonary disease and all had to be euthanized within 72 hours ( FIG. 17 ). Lungs of mock-treated mice all contained greater than 10 6  cfu of  B. pseudomallei  at the time of euthanasia. In contrast, none of the NS398-treated mice showed signs of illness until day 5 post-infection. On day 5, one mouse in the NS398-treated group displayed hind leg paralysis and was humanely euthanized. This was observed again in another animal on day 7. No bacteria were recovered from the lungs of either animal. Intranasal infection of mice with  B. pseudomallei  often manifests in colonization of the brain with subsequent neurologic complication, and we believe that this, and not pulmonary disease, likely accounted for the animals&#39; morbidity. By day 10, all of the remaining NS398-treated mice appeared to have recovered from the infection. NS398-treated mice showed no evidence of weight loss throughout the study (data not shown). No bacteria were recovered from the lungs of NS398-treated mice at the study endpoint with the exception of one animal that contained 104 cfu. All of the mice were colonized with 20-100 cfu in the spleen and liver, indicating that bacterial dissemination from the lung had occurred. These results indicate that host PGE-2 production promotes the pathogenesis of  B. pseudomallei  during pneumonic melioidosis and that inhibition of COX-2 enhances bacterial clearance from the lung and improves host survival. 
     Consistent with these findings, COX-2 inhibition also reduced tissue bacterial burdens and pulmonary inflammation in mice infected with  B. thailandensis  ( FIGS. 18-19 ). In order to compare the inflammatory responses in the lungs of drug- and mock-treated mice, histological and cytokine analyses were performed on lung tissue obtained 48 hours post-challenge. Histological examination showed no evidence of pulmonary inflammation in naïve, uninfected mice, as shown in  FIG. 18 . In contrast, severe inflammatory cell infiltration was apparent in the peri-bronchial and peri-vascular regions of the lungs following Bt challenge. The inflammation was reduced in the Celecoxib-treated mice with less evidence of inflammatory cells than mock-treated mice, as shown by  FIG. 18 . 
     To explore the role of PGE-2 during acute melioidosis, mice were orally administered the COX-2 inhibitor Celecoxib or a mock control of DMSO four hours prior to bacterial challenge. Bacterial burdens in lung, liver, and spleen were determined at 48 hours post-infection. Mice that received the COX-2 inhibitor demonstrated a reduction in bacterial burdens in all tissues examined compared to mock-treated mice, as shown in  FIGS. 19A, 19B , and  19 C. PGE-2 reduction in the lungs of Celecoxib-treated mice was confirmed by ELISA, as shown in  FIG. 19D . Together, these data indicate that induction of endogenous COX-2 and PGE-2 by Bt suppresses bacterial clearance in vivo. 
     Example B6—Effect of COX-2 Inhibition on Lung Arginase 
       B. pseudomallei  infection led to increased PGE-2 and Arg2 expression in macrophages and both PGE-2 and Arg2 enhanced  B. pseudomallei  intracellular survival. Furthermore, PGE-2 positively regulated Arg2 expression in response to  B. pseudomallei  in vitro. We therefore evaluated Arg2 expression in the lungs of mice in response to bacterial infectious disease and COX-2 inhibition. Similar to our in vitro observations, an increase in lung Arg2, but not Arg1, was observed in  B. pseudomallei -infected animals compared to uninfected animals ( FIG. 20 ). Upon COX-2 inhibition, a reduction in lung Arg2 was observed in  B. pseudomallei -infected mice as evident by Western blot and densitometry analysis ( FIG. 20 ). These results corroborate our observations in murine macrophages and advocate a supporting role for Arg2 in PGE-2-mediated immunosuppression during  B. pseudomallei  infection. 
     EXAMPLE SET C 
     Example C1—Exogenous PGE-2 Reduces IFN-γ and IL-2 Production by Stimulated CD4+ T-Cells 
     Methods: CD4+ T cells were purified from spleens of naïve C57B1/6 mice using negative selection. T-cells were then incubated in RPMI (unstimulated) or RPMI plus immobilized Anti-CD3, Anti-cd28, and IL-2 (stimulated) or RPMI plus immobilized Anti-CD3, Anti-cd28, and IL-2 PLUS low dose (100 pg/ml) or high dose (10,000 pg/ml) PGE-2. On Day 3, Cells were spun down and resuspended in fresh media with the appropriate above conditions. On Day 6, cells were harvested, fixed, plugged, and stained for surface markers and intracellular IL-2 and IFN-gamma. 
       FIG. 21A  shows that exogenous PGE-2 reduces IFN-gamma and IL-2 production by stimulated CD4+ T-cells. The percent of CD4+ T-cells is significantly statistically different when comparing unstimulated, low dose PGE-2, high dose PGE-2 to stimulated, as indicated by **p&lt;0.01, ***p&lt;0.001, or ****p&lt;0.0001. 
     Example C2—Supernatant from Bp82-Infected RAW Macrophages Reduces IFN-γ and IL-2 Production by Stimulated CD4+ T-Cells 
     Methods: RAW 267.4 macrophages were grown to confluency and infected with Bp82 at an MOI of 1:1, or stimulated with Bt LPS or left untreated. After 6 hours, cells were spun down and supernatant was collected. CD4+ T cells were purified from spleens of naïve B1/6 mice using negative selection. T-cells were then incubated in RPMI (unstimulated) or RPMI plus immobilized Anti-CD3, Anti-cd28, and IL-2 (stimulated) or RPMI plus immobilized Anti-CD3, Anti-cd28, and IL-2 PLUS 250 μl supernatants from Bp82 infected RAW cells, LPS stimulated RAW cells, or raw cells alone. On Day 3, Cells were spun down and resuspended in fresh media with the same conditions. On Day 6, cells were harvested, fixed, plugged and stained for surface markers and intracellular IL-2 and IFN-gamma. 
       FIG. 21B  shows that the supernatant from RAW cells infected with Bp82 or stimulated with LPS are able to reduce IFN-gamma and IL-2 production by stimulated CD4+ T-cells. The percent of CD4+ T-cells is significantly statistically different when comparing to Bp82 and LPS treated cells to untreated RAW cells, as indicated by *p&lt;0.05, **p&lt;0.01, ***p&lt;0.001, or ****p&lt;0.0001. 
     Example C3—COX-2 Reduces PGE-2 and Suppresses Growth in  B. pseudomallei  in Lung and Stomach Tissue 
     Methods: At time point zero, 4 BALB/C mice were infected with  B. pseudomallei  via aerosol challenge, at a dose of 1.48×10 −7  CFU/mL. Three hours post infection, 2 mice (n=2) were administered NS398 (a COX-2 inhibitor) i.p. at a dose of 15 mg/kg dissolved in DMSO, for a total injection volume of 50 Tμl. Two mice were mock treated with DMSO (n=2). At 24 hours after the first treatment (27 hours post-infection), each mouse was again administered 15 mg/kg NS398 or mock treated with DMSO. A third administration of treatment of the same dosage or mock treatment was given 24 hours after the second treatment (51 hours post-infection). 
     At time of death, stomach, lungs, liver, and spleen were taken from each mouse, homogenized, and plated on PIA agar. CFU/mg of lung and stomach are shown in  FIGS. 22C and 22D , as discussed below. 
     The homogenized stomach and lungs were filtered and determined to be sterile. Filtrate was then stored in −20° C. for further analysis of PGE-2 concentration. PGE-2 concentration of each organ homogenate was analyzed using a PGE-2 ELISA kit (ThermoScientific). Concentrations of PGE-2 in pg/ml in the lung and stomach are shown in  FIGS. 22A and 22B , as discussed below. 
     Concentrations of PGE-2 in pg/ml in the lung for each group of mice can be seen in  FIG. 22A .  FIG. 22A  shows that NS398, a commercially available COX-2 inhibitor, was able to reduce PGE-2 concentration in lung tissue in treated mice, as compared to mice without NS398 treatment. 
     Concentrations of PGE-2 in pg/ml in the stomach for each group of mice can be seen in  FIG. 22B .  FIG. 22B  shows that NS398, a commercially available COX-2 inhibitor, was able to reduce PGE-2 concentration in stomach tissue in treated mice, as compared to mice without NS398 treatment. 
     CFU/mg of lung from each group can be seen in  FIG. 22C .  FIG. 22C  shows that treatment of mice with NS398 suppresses the growth of  B. pseudomallei  in lung tissue during aerosol challenge with the bacteria, when compared to mice that were not treated with NS398. 
     CFU/mg of stomach from each group can be seen in  FIG. 22D .  FIG. 22D  shows that treatment of mice with NS398 suppresses the growth of  B. pseudomallei  in stomach tissue during aerosol challenge with the bacteria, when compared to mice that were not treated with NS398. 
     The headings used in the disclosure are not meant to suggest that all disclosure relating to the heading is found within the section that starts with the heading. Disclosure for any subject may be found throughout the specification. 
     As used in the disclosure and the claims, the term “about” applies to all numeric values, whether or not explicitly indicated. The term “about” generally refers to a range of numbers that one would consider equivalent to the recited value (i.e., having the same function or result). In some instances, the term “about” may include numbers that are rounded to the nearest significant figure. 
     It is noted that terms like “preferably,” “commonly,” and “typically” are not used herein to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present invention. 
     As used in the disclosure, “a” or “an” means one or more than one, unless otherwise specified. As used in the claims, when used in conjunction with the word “comprising” the words “a” or “an” means one or more than one, unless otherwise specified. As used in the disclosure or claims, “another” means at least a second or more, unless otherwise specified. As used in the disclosure, the phrases “such as”, “for example”, and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as”, “for example”, or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list. The word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, “comprising” does not exclude additional unrecited steps or elements. 
     Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein (even if designated as preferred or advantageous) are not to be interpreted as limiting, but rather are to be used as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate manner.