bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone
Authors: Calbo Esther , Alsina Montserrat , Rodríguez-Carballeira Mónica , Lite Josep , Garau Javier 
Published: April 2008

ABSTRACT

Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1β, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-α, for which lower concentrations were obtained at 120 h in the levofloxacin group (
P
= 0.014). Basal oxygen saturation (
P
= 0.034) and heart rate (
P
= 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a β-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.
Activities and Ultrastructural Effects of Antifungal Combinations against Simulated
Candida
Endocardial Vegetations
Authors: Pai Manjunath P. , Samples Marie L. , Mercier Renee-Claude , Spilde Michael N. 
Published: April 2008

ABSTRACT

In vitro pharmacodynamic model (PDM) simulation of serum antifungal concentrations may predict the value of combination antifungal regimens against
Candida
sp. endocarditis. We investigated the effects of combinations of flucytosine (5FC), micafungin (Mica), and voriconazole (Vor) against
Candida
-infected human platelet-fibrin clots, used as simulated endocardial vegetations (SEVs). Single clinical bloodstream isolates of
Candida albicans
,
Candida glabrata
,
Candida parapsilosis
, and
Candida tropicalis
were used. All four isolates were susceptible to 5FC, while
C. glabrata
was resistant to Vor and
C. tropicalis
had a paradoxical resistance phenotype to Mica. The SEVs were prepared with an initial inoculum of 1 × 10
6
CFU/g of SEV and added to a PDM, which utilized yeast nitrogen broth-2% glucose and incubation at 35°C and simulated antifungal pharmacokinetic profiles. Fungal densities in the SEVs were determined in quadruplicate over 72 h. Scanning electron microscopy (SEM) was used to evaluate treatment and control SEVs. Vor was the least active single agent against all
Candida
spp. except for
C. parapsilosis
, where it was comparable to Mica. In contrast, 5FC was the most active against all
Candida
spp. except for
C. tropicalis
, where it was comparable to Mica. The combination of 5FC plus Vor was superior to either agent alone against
C. parapsilosis
. The combination of Vor plus Mica was inferior to the use of Mica alone against
C. tropicalis
. The triple combination of 5FC plus Vor plus Mica was no better than single or dual agents against any of the
Candida
spp. The ultrastructural features of infected SEVs were unique for each
Candida
sp., with
C. parapsilosis
in particular manifesting friable biofilm clusters. In general, 5FC and Mica were superior in their rates and extents of fungal burden reduction compared to Vor against
Candida
-infected SEVs. Evaluation of 5FC and Mica in animal models of
Candida
endocarditis is warranted.
Impact of Mycophenolic Acid on the Functionality of Human Polymorphonuclear Neutrophils and Dendritic Cells during Interaction withAspergillus fumigatus
Authors: Mezger Markus , Wozniok Iwona , Blockhaus Christian , Kurzai Oliver , Hebart Holger , Einsele Hermann , Loeffler Juergen 
Published: April 2008

ABSTRACTMycophenolic acid (MPA) is used clinically to prevent graft rejection but may increase the risk of fungal infection. We observed that MPA enhanced theAspergillus fumigatus-induced oxidative burst of polymorphonuclear neutrophils, but without a corresponding increase in fungal killing. Furthermore, MPA inhibited the proinflammatory cytokine response and maturation of dendritic cells.
CCL28 Is Increased in Human
Helicobacter pylori
-Induced Gastritis and Mediates Recruitment of Gastric Immunoglobulin A-Secreting Cells
Authors: Hansson Malin , Hermansson Michael , Svensson Helena , Elfvin Anders , Hansson Lars-Erik , Johnsson Erik , Sjöling Åsa , Quiding-Järbrink Marianne 
Published: April 2008

ABSTRACT

Human
Helicobacter pylori
infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only
H. pylori
-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosa-associated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in
H. pylori
-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from
H. pylori
-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA
+
memory B cells from
H. pylori
-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from
H. pylori
-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1α). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in
H. pylori
-infected individuals.
Expression of
Staphylococcus epidermidis
SdrG Increases following Exposure to an In Vivo Environment
Authors: Sellman Bret R. , Timofeyeva Yekaterina , Nanra Jasdeep , Scott Adrienne , Fulginiti James P. , Matsuka Yury V. , Baker Steve M. 
Published: April 2008

ABSTRACT

SdrG is a surface-associated fibrinogen binding protein present in most strains of
Staphylococcus epidermidis
. Surface expression of SdrG was not detected by flow cytometry or immunofluorescence microscopy on
S. epidermidis
0-47 grown in nutrient broth or in the presence of human serum.
sdrG
transcript levels increased 1 hour following a shift from growth in nutrient broth to growth in the bloodstream of a mouse and resulted in a concomitant increase in protein levels as detected by immunofluorescence microscopy. The environmental signal(s) resulting in the increase in expression is elusive, as growth under conditions known to mimic in vivo conditions (elevated CO
2
, iron limitation, human serum, and citrated human blood) did not affect expression of SdrG. Immunizing mice with either the N1N2N3 (amino acids 50 to 597) or N2N3 (amino acids 273 to 597) subdomain of the N-terminal A domain of recombinant SdrG (rSdrG) elicited a robust antibody response; however, only mice vaccinated with rSdrG
N23
exhibited a significant reduction in 0-47 recovered after experimental infection. Since SdrG is expressed early during infection in response to specific host environmental cues present in the bloodstream and since antibodies to it are effective in reducing bacteremia, SdrG possesses attributes of a vaccine component effective against the pathogenic form of the ubiquitous human commensal
S. epidermidis
.
Immunogenicity and Protective Efficacy of Recombinant
Campylobacter jejuni
Flagellum-Secreted Proteins in Mice
Authors: Baqar Shahida , Applebee Lisa A. , Gilliland Theron C. , Lee Lanfong H. , Porter Chad K. , Guerry Patricia 
Published: April 2008

ABSTRACT

Immunogenicity and protective efficacy of three
Campylobacter jejuni
flagellum-secreted proteins, FlaC, FspA1, and FspA2, were compared by use of a mouse model. Mice were immunized intranasally with each protein with or without LTR192G as the adjuvant and challenged intranasally with
C. jejuni
81-176 or CG8486. All three proteins were immunogenic, although FspA1 induced the highest levels of serum immunoglobulin G (IgG) and fecal IgA. Although immunogenic, FlaC provided only 18% protection against disease from
C. jejuni
81-176. Immunization with FspA1 resulted in 57.8% protection without adjuvant or 63.8% protection with adjuvant against homologous challenge with 81-176. Alternatively, immunization with FspA2 provided 38.4% (without adjuvant) or 47.2% (with adjuvant) protection against disease from homologous challenge with CG8486. In contrast to FspA2, FspA1 provided some heterologous protection against
C. jejuni
CG8486 when delivered with (31.2%) or without (44.8%) LTR192G. These results suggest that FspA1 may be a good subunit vaccine candidate against
C. jejuni
disease.
Role of Aromatic Amino Acids in Receptor Binding Activity and Subunit Assembly of the Cytolethal Distending Toxin of
Aggregatibacter actinomycetemcomitans
Authors: Cao Linsen , Bandelac Georges , Volgina Alla , Korostoff Jonathan , DiRienzo Joseph M. 
Published: April 2008

ABSTRACT

The periodontal pathogen
Aggregatibacter actinomycetemcomitans
produces a cytolethal distending toxin (Cdt) that inhibits the proliferation of oral epithelial cells. Structural models suggest that the CdtA and CdtC subunits of the Cdt heterotrimer form two putative lectin domains with a central groove. A region of CdtA rich in heterocyclic amino acids (aromatic patch) appears to play an important role in receptor recognition. In this study site-specific mutagenesis was used to assess the contributions of aromatic amino acids (tyrosine and phenylalanine) to receptor binding and CdtA-CdtC assembly. Predominant surface-exposed aromatic residues that are adjacent to the aromatic patch region in CdtA or are near the groove located at the junction of CdtA and CdtC were studied. Separately replacing residues Y105, Y140, Y188, and Y189 with alanine in CdtA resulted in differential effects on binding related to residue position within the aromatic region. The data indicate that an extensive receptor binding domain extends from the groove across the entire face of CdtA that is oriented 180° from the CdtB subunit. Replacement of residue Y105 in CdtA and residues Y61 and F141 in CdtC, which are located in or at the periphery of the groove, inhibited toxin assembly. Taken together, these results, along with the lack of an aromatic amino acid-rich region in CdtC similar to that in CdtA, suggest that binding of the heterotoxin to its cell surface receptor is mediated predominantly by the CdtA subunit. These findings are important for developing strategies designed to block the activity of this prominent virulence factor.
Late Endocytic Multivesicular Bodies Intersect the Chlamydial Inclusion in the Absence of CD63
Authors: Beatty Wandy L. 
Published: April 2008

ABSTRACT
Chlamydiae are obligate intracellular bacterial pathogens that replicate solely within a membrane-bound vacuole termed an inclusion. Within the confines of the inclusion, the replicating bacteria acquire amino acids, nucleotides, and other precursors from the host cell. Trafficking from CD63-positive multivesicular bodies to the inclusion was previously identified as a novel interaction that provided essential precursors for the maintenance of a productive intracellular infection. The present study analyzes the direct delivery of resident protein and lipid constituents of multivesicular bodies to the intracellular chlamydiae. The manipulation of this trafficking pathway with an inhibitor of multivesicular body transport and the delivery of exogenous antibodies altered protein and cholesterol acquisition and delayed the maturation of the chlamydial inclusion. Although inhibitor studies and ultrastructural analyses confirmed a novel interaction between CD63-positive multivesicular bodies and the intracellular chlamydiae, neutralization with small interfering RNAs and anti-CD63 Fab fragments revealed that CD63 itself was not required for this association. These studies confirm CD63 as a constituent in multivesicular body-to-inclusion transport; however, other requisite components of these host cell compartments must control the delivery of key nutrients that are essential to intracellular bacterial development.
Impact of Mating Type, Serotype, and Ploidy on the Virulence of
Cryptococcus neoformans
Authors: Lin Xiaorong , Nielsen Kirsten , Patel Sweta , Heitman Joseph 
Published: April 2008

ABSTRACT

Hybridization with polyploidization is a significant biological force driving evolution. The effect of combining two distinct genomes in one organism on the virulence potential of pathogenic fungi is not clear.
Cryptococcus neoformans
, the most common cause of fungal infection of the central nervous system, has a bipolar mating system with
a
and α mating types and occurs as A (haploid), D (haploid), and AD hybrid (mostly diploid) serotypes. Diploid AD hybrids are derived either from
a
-α mating or from unisexual mating between haploid cells. The precise contributions of increased ploidy, the effect of hybridization between serotypes A and D, and the combination of mating types to the virulence potential of AD hybrids have remained elusive. By using in vitro and in vivo characterization of laboratory-constructed isogenic diploids and AD hybrids with all possible mating type combinations in defined genetic backgrounds, we found that higher ploidy has a minor negative effect on virulence in a murine inhalation model of cryptococcosis. The presence of both mating types
a
and α in AD hybrids did not affect the virulence potential, irrespective of the serotype origin. Interestingly, AD hybrids with only one mating type behaved differently, with the virulence of αADα strains similar to that of other hybrids, while
a
AD
a
hybrids displayed significantly lower virulence due to negative epistatic interactions between the A
a
and D
a
alleles of the mating type locus. This study provides insights into the impact of ploidy, mating type, and serotype on virulence and the impact of hybridization on the fitness and virulence of a eukaryotic microbial pathogen.
Deficiency of Indoleamine 2,3-Dioxygenase Enhances Commensal-Induced Antibody Responses and Protects against
Citrobacter rodentium
-Induced Colitis
Authors: Harrington Lynne , Srikanth Chittur V. , Antony Reuben , Rhee Sue J. , Mellor Andrew L. , Shi Hai Ning , Cherayil Bobby J. 
Published: April 2008

ABSTRACT

Indoleamine 2,3-dioxygenase (IDO) is a negative regulator of lymphocyte responses that is expressed predominantly in macrophages and dendritic cells. We detected it at high levels in the small intestine and mesenteric lymph node of young adult mice, suggesting a role in intestinal immunity. Consistent with this idea, we found that IDO-deficient mice had elevated baseline levels of immunoglobulin A (IgA) and IgG in the serum and increased IgA in intestinal secretions. These abnormalities were corrected by a course of broad-spectrum oral antibiotics started at weaning, indicating that they were dependent on the intestinal microbiota. Kynurenine and picolinic acid, two IDO-generated metabolites of tryptophan, were able to inhibit lipopolysaccharide-induced antibody production by splenocytes in vitro, and kynurenine also induced B-cell apoptosis, findings that provide an explanation for the elevated Ig levels in animals lacking IDO. The intestinal secretions of IDO-deficient mice had elevated levels of IgA antibodies that cross-reacted with the gram-negative enteric bacterial pathogen
Citrobacter rodentium
. In keeping with the functional importance of this natural secretory IgA, the mutant animals were more resistant to intestinal colonization by
Citrobacter
, developed lower levels of serum
Citrobacter
-specific IgM and IgG antibodies following oral infection, and had significantly attenuated
Citrobacter
-induced colitis. Our observations point to an important role for IDO in the regulation of immunity to the gut commensal microbiota that has a significant impact on the response to intestinal pathogens.
Serendipitous Discovery of an Immunoglobulin-Binding Autotransporter in
Bordetella
Species
Authors: Williams Corinne L. , Haines Robert , Cotter Peggy A. 
Published: April 2008

ABSTRACT

We describe the serendipitous discovery of BatB, a classical-type
Bordetella
autotransporter (AT) protein with an ∼180-kDa passenger domain that remains noncovalently associated with the outer membrane. Like genes encoding all characterized protein virulence factors in
Bordetella
species,
batB
transcription is positively regulated by the master virulence regulatory system BvgAS. BatB is predicted to share similarity with immunoglobulin A (IgA) proteases, and we showed that BatB binds Ig in vitro. In vivo, a
Bordetella bronchiseptica
Δ
batB
mutant was unable to overcome innate immune defenses and was cleared from the lower respiratory tracts of mice more rapidly than wild-type
B. bronchiseptica
. This defect was abrogated in SCID mice, suggesting that BatB functions to resist clearance during the first week postinoculation in a manner dependent on B- and T-cell-mediated activities. Taken together with the previous demonstration that polymorphonuclear neutrophils (PMN) are critical for the control of
B. bronchiseptica
in mice, our data support the hypothesis that BatB prevents nonspecific antibodies from facilitating PMN-mediated clearance during the first few days postinoculation. Neither of the strictly human-adapted
Bordetella
subspecies produces a fully functional BatB protein; nucleotide differences within the putative promoter region prevent
batB
transcription in
Bordetella pertussis
, and although expressed, the
batB
gene of human-derived
Bordetella parapertussis
(
B. parapertussis
hu
) contains a large in-frame deletion relative to
batB
of
B. bronchiseptica
. Taken together, our data suggest that BatB played an important role in the evolution of virulence and host specificity among the mammalian-adapted bordetellae.
Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block
Authors: Welin Amanda , Winberg Martin E. , Abdalla Hana , Särndahl Eva , Rasmusson Birgitta , Stendahl Olle , Lerm Maria 
Published: April 2008

ABSTRACTLipoarabinomannan (LAM) is one of the key virulence factors forMycobacterium tuberculosis, the etiological agent of tuberculosis. During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage and can be detected throughout the cell upon infection. LAM can inhibit phagosomal maturation as well as induce a proinflammatory response in bystander cells. The aim of this study was to investigate how LAM exerts its action on human macrophages. We show that LAM is incorporated into membrane rafts of the macrophage cell membrane via its glycosylphosphatidylinositol anchor and that incorporation of mannose-capped LAM fromM. tuberculosisresults in reduced phagosomal maturation. This is dependent on successful insertion of the glycosylphosphatidylinositol anchor. LAM does not, however, induce the phagosomal maturation block through activation of p38 mitogen-activated protein kinase, contradicting some previous suggestions.
Type IV Pili inFrancisella tularensis: Roles ofpilFandpilTin Fiber Assembly, Host Cell Adherence, and Virulence
Authors: Chakraborty Subhra , Monfett Michael , Maier Tamara M. , Benach Jorge L. , Frank Dara W. , Thanassi David G. 
Published: April 2008

ABSTRACTFrancisella tularensis, a highly virulent facultative intracellular bacterium, is the causative agent of tularemia. Genome sequencing of allF. tularensissubspecies revealed the presence of genes that could encode type IV pili (Tfp). The live vaccine strain (LVS) expresses surface fibers resembling Tfp, but it was not established whether these fibers were indeed Tfp encoded by thepilgenes. We show here that deletion of thepilFputative Tfp assembly ATPase in the LVS resulted in a complete loss of surface fibers. Disruption of thepilTputative disassembly ATPase also caused a complete loss of pili, indicating thatpilTfunctions differently inF. tularensisthan in model Tfp systems such as those found inPseudomonas aeruginosaandNeisseriaspp. The LVSpilFandpilTmutants were attenuated for virulence in a mouse model of tularemia by the intradermal route. Furthermore, although absence of pili had no effect on the ability of the LVS to replicate intracellularly, thepilFandpilTmutants were defective for adherence to macrophages, pneumocytes, and hepatocytes. This work confirms that the surface fibers expressed by the LVS are encoded by thepilgenes and provides evidence that theFrancisellapili contribute to host cell adhesion and virulence.
Comparison of the Contributions of Heat-Labile Enterotoxin and Heat-Stable Enterotoxin b to the Virulence of EnterotoxigenicEscherichia coliin F4ac Receptor-Positive Young Pigs
Authors: Erume Joseph , Berberov Emil M. , Kachman Stephen D. , Scott Michael A. , Zhou You , Francis David H. , Moxley Rodney A. 
Published: April 2008

ABSTRACTIn swine, the most common and severe enterotoxigenicEscherichia coli(ETEC) infections are caused by strains that express K88 (F4)+fimbriae, heat-labile enterotoxin (LT), heat-stable enterotoxin b (STb), and enteroaggregativeE. coliheat-stable toxin 1. Previous studies based on a design that involved enterotoxin genes cloned into a nontoxigenic fimbriated strain have suggested that LT but not STb plays an important role in dehydrating diarrheal disease in piglets <1 week old and also enhances bacterial colonization of the intestine. In the present study, we compared these two toxins in terms of importance for piglets >1 week old with a study design that involved construction of isogenic single- and double-deletion mutants and inoculation of 9-day-old F4ac receptor-positive gnotobiotic piglets. Based on the postinoculation percent weight change per h and serum bicarbonate concentrations, the virulence of the STb−mutant (ΔestB) did not significantly differ from that of the parent. However, deletion of the LT genes (ΔeltAB) in the STb−mutant resulted in a complete abrogation of weight loss, dehydration, and metabolic acidosis in inoculated pigs, and LT complementation restored the virulence of this strain. These results support the hypothesis that LT is a more significant contributor than STb to the virulence of F4+ETEC infections in young F4ac receptor-positive pigs less than 2 weeks old. However, in contrast to previous studies with gnotobiotic piglets, there was no evidence that the expression of LT enhanced the ability of the F4+ETEC strain to colonize the small intestine.