bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diminished Monocyte Function in Microfilaremic Patients with Lymphatic Filariasis and Its Relationship to Altered Lymphoproliferative Responses
Authors: Sasisekhar B. , Aparna M. , Augustin D. J. , Kaliraj P. , Kar S. K. , Nutman T. B. , Narayanan R. B. 
Published: May 2005

ABSTRACTAntigen-specific hyporesponsiveness to filarial antigens is a phenomenon observed in patent infection with lymph-dwelling filarial parasites of humans. This phenomenon has been attributed to a multitude of factors, one of which is altered monocyte function. To examine the role played by monocytes in filarial infection, we assessed the responses of monocytes obtained from normal and filarial parasite-infected individuals to both crude filarial antigen and purified recombinant filarial antigen WbSXP-1 and attempted to relate these to the altered lymphoproliferative responses seen in filarial infection. Monocytes from microfilaremic (MF) patients demonstrated an inability to respond to lipopolysaccharide compared to monocytes from endemic normal persons or from lymphedema patients. Indeed, interleukin 1β (IL-1β) production was severely limited, a finding that did not extend to monocyte responses to filarial antigens. Serum from MF patients reduced adherence and spreading of normal monocytes, a finding not seen with serum from the other clinical groups. Interestingly, there was a significant correlation between the production of IL-1β and adherence. Moreover, the levels of spontaneous production of IL-1β correlated with high levels of spontaneous secretion of IL-10. The effects observed were not a result of diminished viability or alteration in the expression of the cell surface markers CD14 and HLA-DR. These data suggest that monocyte function is dampened in MF patients, a finding which could alter lymphoproliferative responses during patent infection.
Transcriptional Control of Impaired Th1 Responses in Patent Lymphatic Filariasis by T-Box Expressed in T Cells and Suppressor of Cytokine Signaling Genes
Authors: Babu Subash , Kumaraswami V. , Nutman Thomas B. 
Published: May 2005

ABSTRACTT-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n= 6) and uninfected controls (n= 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-γ) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-γ expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells.
Host Cytokine Production, Lymphoproliferation, and Antibody Responses during the Course of
Ancylostoma ceylanicum
Infection in the Golden Syrian Hamster
Authors: Mendez Susana , Valenzuela Jesus G. , Wu Wenhui , Hotez Peter J. 
Published: May 2005

ABSTRACT

The Syrian Golden hamster (
Mesocricetus auratus
) has been used to model infections with the hookworm
Ancylostoma ceylanicum
. New molecular immunological reagents to measure cellular immune responses in hamsters were developed and used to determine the impact of
A. ceylanicum
hookworm infection on host cytokine responses and lymphoproliferation. Initial larval infection with 100 third-stage
A. ceylanicum
larvae resulted in predominant Th1 responses (upregulation of proinflammatory cytokines) that lasted for the duration of larval migration and continued up to 14 days postinfection (prepatency). Subsequently, development of larvae into egg-laying adult hookworms (patency) coincided with a switch to Th2 predominant responses (interleukin-4 [IL-4]) as well as a marked increase in IL-10 production. This switch also concurred with reduced host lymphoproliferative responses to hookworm antigens. The findings demonstrate a similarity in immune responses between hamsters and humans infected with hookworms, suggesting that hamsters will be a useful animal model species for examining host immunity to human hookworm infections.
Combining Anthrax Vaccine and Therapy: a Dominant-Negative Inhibitor of Anthrax Toxin Is Also a Potent and Safe Immunogen for Vaccines
Authors: Aulinger Benedikt A. , Roehrl Michael H. , Mekalanos John J. , Collier R. John , Wang Julia Y. 
Published: May 2005

ABSTRACT

Anthrax is caused by the unimpeded growth of
Bacillus
anthracis
in the host and the secretion of toxins. The currently available vaccine is based on protective antigen (PA), a central component of anthrax toxin. Vaccination with PA raises no direct immune response against the bacilli and, being a natural toxin component, PA might be hazardous when used immediately following exposure to
B. anthracis
. Thus, we have sought to develop a vaccine or therapeutic agent that is safe and eliminates both secreted toxins and bacilli. To that end, we have previously developed a dually active vaccine by conjugating the capsular poly-γ-
d
-glutamate (PGA) with PA to elicit the production of antibodies specific for both bacilli and toxins. In the present report, we describe the improved potency of anthrax vaccines through the use of a dominant-negative inhibitory (DNI) mutant to replace PA in PA or PA-PGA vaccines. When tested in mice, DNI alone is more immunogenic than PA, and DNI-PGA conjugate elicits significantly higher levels of antibodies against PA and PGA than PA-PGA conjugate. To explain the enhanced immunogenicity of DNI, we propose that the two point mutations in DNI may have improved epitopes of PA allowing better antigen presentation to helper T cells. Alternatively, these mutations may enhance the immunological processing of PA by altering endosomal trafficking of the toxin in antigen-presenting cells. Because DNI has previously been demonstrated to inhibit anthrax toxin, postexposure use of DNI-based vaccines, including conjugate vaccines, may provide improved immunogenicity and therapeutic activity simultaneously.
Role of
Staphylococcus aureus
Global Regulators
sae
and σ
B
in Virulence Gene Expression during Device-Related Infection
Authors: Goerke Christiane , Fluckiger Ursula , Steinhuber Andrea , Bisanzio Vittoria , Ulrich Martina , Bischoff Markus , Patti Joseph M. , Wolz Christiane 
Published: May 2005

ABSTRACT

The ability of
Staphylococcus aureus
to adapt to different environments is due to a regulatory network comprising several loci. Here we present a detailed study of the interaction between the two global regulators
sae
and σ
B
of
S. aureus
and their influence on virulence gene expression in vitro, as well as during device-related infection. The expression of
sae
,
asp23
,
hla
,
clfA
,
coa
, and
fnbA
was determined in strain Newman and its isogenic
saeS/R
and
sigB
mutants by Northern analysis and LightCycler reverse transcription-PCR. There was no indication of direct cross talk between the two regulators.
sae
had a dominant effect on target gene expression during device-related infection. σ
B
seemed to be less active throughout the infection than under induced conditions in vitro.
Entamoeba histolyticaandEntamoeba disparUtilize Externalized Phosphatidylserine for Recognition and Phagocytosis of Erythrocytes
Authors: Boettner Douglas R. , Huston Christopher D. , Sullivan James A. , Petri William A. 
Published: May 2005

ABSTRACTAmebic erythrophagocytosis is characteristic of invasive amebiasis, and mutants deficient in erythrocyte ingestion are avirulent. We sought to understand the molecular mechanisms underlying erythrocyte phagocytosis byEntamoeba histolytica. Following adherence to amebae, erythrocytes became round and crenulated, and phosphatidylserine (PS) was exposed on their outer membrane leaflets. These changes were similar to the effects of calcium treatment on erythrocytes, which we utilized to separate ameba-induced exposure of erythrocyte PS from the process of phagocytosis. The adherence and phagocytosis of calcium-treated erythrocytes were less inhibited by galactose than were those of healthy erythrocytes, suggesting the existence of an amebic coreceptor specific for PS. To test whether PS was recognized by amebae, calcium-treated cells were incubated with annexin V prior to adherence to or ingestion byE. histolytica. Annexin V blocked both adherence (50% ± 12% inhibition;P< 0.05) and phagocytosis (65% ± 10%;P< 0.05), providing evidence that at least one galactose-independent coreceptor was involved in the adherence and ingestion of red blood cells. The coreceptor was inhibited by phospho-l-serine and to a lesser extent by phospho-d-serine but not by phospho-l-threonine, which is consistent with the coreceptor functioning in the adherence and ingestion of erythrocytes via recognition of PS. We expanded our investigations to the highly related but noninvasive parasiteEntamoeba disparand demonstrated that it was deficient in red-blood-cell adherence, induction of PS exposure, and phagocytosis. These findings establish phosphatidylserine involvement in erythrophagocytosis by amebae and suggest the existence of a PS receptor on the surfaces of bothE. histolyticaandE. dispar.
Killing ofdsrAMutants ofHaemophilus ducreyiby Normal Human Serum Occurs via the Classical Complement Pathway and Is Initiated by Immunoglobulin M Binding
Authors: Abdullah Malikah , Nepluev Igor , Afonina Galyna , Ram Sanjay , Rice Peter , Cade William , Elkins Christopher 
Published: May 2005

ABSTRACTPreviously, we showed that serum resistance inHaemophilus ducreyitype strain 35000HP required expression of the outer membrane protein DsrA because the isogenicdsrAmutant FX517 is highly serum susceptible. In this study, we confirmed this finding by construction of additional serum-susceptibledsrA mutants in more recently isolated serum-resistant strains. We also demonstrated that killing ofdsrAmutants required an intact classical complement cascade but not the alternative or mannan-binding lectin pathways. Between 5- and 10-fold more purified human immunoglobulin M (IgM) but not IgG was deposited ontodsrAmutant FX517 than onto parent strain 35000HP, consistent with IgM initiation of the classical cascade. Depletion of IgM, but not IgG, from complement-intact serum inhibited killing of FX517. As predicted from the amounts of IgM bound, more of the individual complement components were bound by FX517 than by parent strain 35000HP. Examination of the binding of negative regulators of complement as an explanation for serum resistance indicated that parent strain 35000HP bound more C4 binding protein and vitronectin than FX517 but not factor H. However, the degree and pattern of complement component binding observed suggested that IgM binding to the serum-susceptible mutant FX517 was responsible for the activation of the classical pathway and the observed killing of FX517 as opposed to binding of negative regulators of complement by the serum-resistant parent. We speculate that an undefined neo-epitope, possibly carbohydrate, is exposed in thedsrAmutant that is recognized by naturally occurring bactericidal IgM antibodies present in human sera.
Coinfection withAnaplasma phagocytophilumAltersBorrelia burgdorferiPopulation Distribution in C3H/HeN Mice
Authors: Holden Kevin , Hodzic Emir , Feng Sunlian , Freet Kimberly J. , Lefebvre Rance B. , Barthold Stephen W. 
Published: May 2005

ABSTRACTBorrelia burgdorferi, the agent of Lyme disease, andAnaplasma phagocytophilum, the agent of human anaplasmosis, are both transmitted byIxodessp. ticks and may occasionally coinfect a host. The population distributions of tick-transmittedB. burgdorferiinfection were assessed using quantitative PCR targeting theflaBgene ofB. burgdorferiin the ear, heart base, quadriceps muscle, skin, and tibiotarsal joint tissue of C3H mice previously infected withA. phagocytophilum. Population distributions ofAnaplasmainfection were assessed by targeting thep44gene.A. phagocytophilumin blood and serologic response to both agents were evaluated. Spirochete numbers were increased in the ears, heart base, and skin of coinfected mice, butAnaplasmanumbers remained constant. Antibody response toA. phagocytophilum, but notB. burgdorferi, was decreased in coinfected mice. These results suggest that coinfection withA. phagocytophilumandB. burgdorferimodulates pathogen burden and host antibody responses. This may be explained by the ability ofA. phagocytophilumto functionally impair neutrophils, important cells in the early defense againstB. burgdorferiinfection.
Gamma Interferon Enhances Internalization and Early Nonoxidative Killing ofSalmonella entericaSerovar Typhimurium by Human Macrophages and Modifies Cytokine Responses
Authors: Gordon Melita A. , Jack Dominic L. , Dockrell David H. , Lee Margaret E. , Read Robert C. 
Published: May 2005

ABSTRACTGamma interferon (IFN-γ) is a critical cytokine in host defense against salmonella infections, but its role in phagocytic killing of intracellularSalmonellaspp. has been investigated mainly in animal rather than human cells. We measured the effect of recombinant IFN-γ (rIFN-γ) priming on bacterial internalization, intracellular killing, oxidative burst, and cytokine release during phagocytosis ofSalmonella entericaserovar Typhimurium by human monocyte-derived macrophages (MDM). Eleven-day-old MDM, primed for 72 h with rIFN-γ (100 ng/ml) exhibited an increased proportion of cells with associated bacteria (31% versus 26%,P= 0.036) and a 67% increase in internalized bacteria per cell compared to unprimed cells (P= 0.025). Retrieval of viable bacteria following internalization was reduced 3.6-fold in 72-h primed versus unprimed MDM (interquartile range, 3.1 to 6.4) at 0.5 h due to enhanced early intracellular killing, and this difference was maintained up to 24 h. In contrast, cells primed for only 24 h exhibited no increase in early killing. MDM were competent to produce an early oxidative burst when stimulated with phorbol myristate acetate, which was fully abrogated by the respiratory burst inhibitor diphenyleneiodonium chloride (DPI), but infection of MDM withS. entericaserovar Typhimurium did not cause an increase in the early respiratory burst under unprimed or primed conditions, and DPI had no effect on the early killing of bacteria by primed or unprimed MDM. During 24 h following infection, rIFN-γ-primed MDM released more interleukin-12 (IL-12) and less IL-10 relative to unprimed cells. We conclude that 72-h priming with rIFN-γ increases the efficiency of internalization and nonoxidative early intracellular killing ofS. entericaserovar Typhimurium by human macrophages and modifies subsequent cytokine release.
Gamma Interferon Positively ModulatesActinobacillus actinomycetemcomitans-Specific RANKL+CD4+Th-Cell-Mediated Alveolar Bone Destruction In Vivo
Authors: Teng Yen-Tung A. , Mahamed Deeqa , Singh Bhagirath 
Published: May 2005

ABSTRACTRecent studies have shown the biological and clinical significance of signaling pathways of osteogenic cytokines RANKL-RANK/OPG in controlling osteoclastogenesis associated with bone pathologies, including rheumatoid arthritis, osteoporosis, and other osteolytic disorders. In contrast to the inhibitory effect of gamma interferon (IFN-γ) on RANKL-mediated osteoclastogenesis reported recently, alternative new evidence is demonstrated via studies of experimental periodontitis using humanized NOD/SCID and diabetic NOD mice and clinical human T-cell isolates from diseased periodontal tissues, where the presence of increasing IFN-γ is clearly associated with (i) enhancedActinobacillus actinomycetemcomitans-specific RANKL-expressing CD4+Th cell-mediated alveolar bone loss during the progression of periodontal disease and (ii) a concomitant and significantly increased coexpression of IFN-γ in RANKL(+) CD4+Th cells. Therefore, there are more complex networks in regulating RANKL-RANK/OPG signaling pathways for osteoclastogenesis in vivo than have been suggested to date.
Distinct Th1- and Th2-Type Prenatal Cytokine Responses toPlasmodium falciparumErythrocyte Invasion Ligands
Authors: Malhotra Indu , Mungai Peter , Muchiri Eric , Ouma John , Sharma Shobhona , Kazura James W. , King Christopher L. 
Published: May 2005

ABSTRACTPrenatal immunity toPlasmodium falciparummerozoite proteins involved in erythrocyte invasion may contribute to the partial protection against malaria that is acquired during infancy in areas of stable malaria transmission. We examined newborn and maternal cytokine and antibody responses to merozoite surface protein-1 (MSP-1), ribosomal phosphoprotein P0 (PfP0), and region II of erythrocyte binding antigen-175 (EBA-175) in infant-mother pairs in Kenya. Overall, 82 of 167 (50%), 106 of 176 (60%), and 38 of 84 (45%) cord blood lymphocytes (CBL) from newborns produced one or more cytokines in response to MSP-1, PfP0, and EBA-175, respectively. Newborns of primigravid and/or malaria-infected women were more likely to have antigen-responsive CBL than were newborns of multigravid and/or uninfected women at delivery. Newborn cytokine responses did not match those of their mothers and fell into three distinct categories, Th1 (21 of 55 CBL donors produced only gamma interferon and/or interleukin 2 [IL-2]), Th2 (21 of 55 produced only IL-5 and/or IL-13), and mixed Th1/Th2 (13 of 55). Newborns produced more IL-10 than adults. High and low levels of cord blood IL-12 p70 production induced by anti-CD40 activation were associated with malaria-specific Th1 and Th2 responses, respectively. Antigen-responsive CBL in some newborns were detected only after depletion of IL-10-secreting CD8 cells with enrichment for CD4 cells. These data indicate that prenatal sensitization to blood-stagePlasmodium falciparumoccurs frequently in areas where malaria is holoendemic. Modulation of this immunity, possibly by maternal parity and malaria, may affect the acquisition of protective immunity against malaria during infancy.
Identification of Surface Antigens of
Moraxella catarrhalis
as Targets of Human Serum Antibody Responses in Chronic Obstructive Pulmonary Disease
Authors: Murphy Timothy F. , Brauer Aimee L. , Aebi Christoph , Sethi Sanjay 
Published: May 2005

ABSTRACT

Moraxella catarrhalis
is an important respiratory tract pathogen, causing otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). Adults with COPD make antibody responses to
M. catarrhalis
following infection, but little is known about the identity of the antigens to which these antibodies are directed. In this study, 12 serum samples obtained from adults with COPD who had cleared
M. catarrhalis
from the respiratory tract following infection and who had developed new serum immunoglobulin G (IgG) to their infecting strain were subjected to a series of assays to identify the antigens to which potentially protective antibodies were directed. Sera were adsorbed with intact bacterial cells, and antibodies were eluted from the surfaces of the bacteria. Analysis by flow cytometry established that adsorption and elution effectively detected antibodies specifically directed to surface-exposed epitopes. Immunoblot assays of adsorbed and eluted serum fractions were performed with purified outer membranes and purified lipooligosaccharide of homologous infecting strains and with a series of mutants deficient in expression of individual outer membrane proteins (OMPs). While heterogeneity in antibody responses among individuals was observed, five major OMPs, UspA1, UspA2, Hag, TbpB, and OMP CD, were identified as targets of antibodies to surface epitopes in the majority of adults with COPD who cleared the organism. These results have important implications in understanding human immune responses to
M. catarrhalis
and in elucidating the elements of a protective immune response.
Identification, Distribution, and Expression of Novel Genes in 10 Clinical Isolates of Nontypeable
Haemophilus influenzae
Authors: Shen Kai , Antalis Patricia , Gladitz John , Sayeed Sameera , Ahmed Azad , Yu Shujun , Hayes Jay , Johnson Sandra , Dice Bethany , Dopico Richard , Keefe Randy , Janto Benjamin , Chong William , Goodwin Joseph , Wadowsky Robert M. , Erdos Geza , Post J. Christopher , Ehrlich Garth D. , Hu Fen Z. 
Published: May 2005

ABSTRACT

We hypothesize that
Haemophilus influenzae
, as a species, possesses a much greater number of genes than that found in any single
H. influenzae
genome. This supragenome is distributed throughout naturally occurring infectious populations, and new strains arise through autocompetence and autotransformation systems. The effect is that
H. influenzae
populations can readily adapt to environmental stressors. The supragenome hypothesis predicts that significant differences exist between and among the genomes of individual infectious strains of nontypeable
H.
influenzae
(NTHi). To test this prediction, we obtained 10 low-passage NTHi clinical isolates from the middle ear effusions of patients with chronic otitis media. DNA sequencing was performed with 771 clones chosen at random from a pooled genomic library. Homology searching demonstrated that ∼10% of these clones were novel compared to the
H. influenzae
Rd KW20 genome, and most of them did not match any DNA sequence in GenBank. Amino acid homology searches using hypothetical translations of the open reading frames revealed homologies to a variety of proteins, including bacterial virulence factors not previously identified in the NTHi isolates. The distribution and expression of 53 of these genes among the 10 strains were determined by PCR- and reverse transcription PCR-based analyses. These unique genes were nonuniformly distributed among the 10 isolates, and transcription of these genes in planktonic cultures was detected in 50% (177 of 352) of the occurrences. All of the novel sequences were transcribed in one or more of the NTHi isolates. Seventeen percent (9 of 53) of the novel genes were identified in all 10 NTHi strains, with each of the remaining 44 being present in only a subset of the strains. These genic distribution analyses were more effective as a strain discrimination tool than either multilocus sequence typing or 23S ribosomal gene typing methods.