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Inducible Costimulator Contributes to Methicillin-Resistant Staphylococcus aureus Pneumonia.

ABSTRACT: Staphylococcus aureus is a major cause of both community- and healthcare-acquired pneumonias. Inducible costimulator (ICOS) is part of the CD28 family of proteins and is a target for immune checkpoint therapy. We found ICOS highly expressed on activated CD4 cells in response to S. aureus. In the absence of ICOS, mice had improved survival in a pneumonia model with the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 and significant reductions in bacterial burden in a nonlethal acute pneumonia model. Infected Icos-/- mice had major reductions in several proinflammatory cytokines, neutrophils, inflammatory monocytes, and eosinophils compared to infected wild-type mice, while there was improved expression of CD11c and macrophage receptor with collagenous structure on the surface of alveolar macrophages. Early during infection infected Icos-/- mice had increased numbers of alveolar macrophages and expression of several surface markers on alveolar macrophages and neutrophils. ICOS signaling also contributed to the pathogenesis of the airway pathogens Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus pneumoniae, and neutralizing antibody to ICOS led to improved clearance of S. aureus from the airway. Our results indicate that ICOS plays a significant role in orchestrating the innate immune response to S. aureus and other airway pathogens, and could be a potential immunomodulatory target to attenuate S. aureus-related immunopathology.

SUBMITTER: Pires S

PROVIDER: S-EPMC6047441 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Project description:Staphylococcus aureus, an important nosocomial pathogen, is frequently associated with infections in human. The management of the infections by it especially methicillin resistant ones is often difficult because methicillin resistant S. aureus is usually resistant to multiple antibiotics. Macrolide-lincosamide streptogramin B family of antibiotics is commonly used to treat such infections as an alternative to vancomycin.This study was conducted over the period of one and half year from November 2013-April 2015 in Microbiology laboratory of Nepal Medical College and Teaching Hospital, Kathmandu, Nepal to find the incidence of different phenotypes of MLSB resistance among S. aureus from clinical samples and their association with methicillin resistance. Two hundred seventy isolates of S. aureus were included in the study. Methicillin resistance was detected by cefoxitin disc diffusion method and inducible clindamycin resistance by erythromycin and clindamycin disc approximation test (D-test).Of the 270 clinical isolates of S. aureus, 25.1% (68/270) were MRSA. Erythromycin and clindamycin resistance was seen in 54.4% (147/270) and 41.8% (113/270) isolates respectively. Resistance to erythromycin and clindamycin were higher in MRSA as compared to MSSA (erythromycin-resistance: 88.2% Vs 39.1% and clindamycin-resistance: 79.4% Vs 41.8%). The overall prevalence of iMLSB and cMLSB phenotype was 11.48% (31/270) and 29.25% (79/270) respectively. Both iMLSB and cMLSB phenotypes predominated in MRSA strains.Detection rate of MRSA in our study shows the necessity to improve in healthcare practices and to formulate new policy for the control of MRSA infections. Clindamycin resistance in the form of iMLSB and cMLSB especially among MRSA emphasizes the need of D-test to be performed routinely in our set up while using clindamycin as an alternative choice to anti-staphylococcal antibiotics like vancomycin and linezolid in the treatment of staphylococcal infections.

Project description:Methicillin resistant Staphylococcus aureus (MRSA) infection is becoming refractory to existing antibiotic therapy owing to the inherent ability of S. aureus to develop rapid resistance and is considered a major threat to public health. We found that a natural isolate of Bacillus pumilus from the Columbia River Estuary produces a strong anti-MRSA compound, amicoumacin A. As amicoumacin A has been reported to exhibit anti-microbial, anti-inflammatory, and anti-ulcer activities, we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in the expression of genes involved in several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which has been shown to be induced in response to a collapse of membrane potential. In order to gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by serial passage method was carried out. Single point mutations resulting in codon substitutions were uncovered in several distinct genes: ksgA, RNA dimethyltranferase; fusA, elongation factor G; dnaG, primase, ; lacD, tagatose 1,6-bisphosphate aldolase, ; and SACOL0611, encoding a putative glycosyl transferase gene. Based on these results, a candidate approach was undertaken to recreate the same amino acid substitution individually in FusA and KsgA, each of which resulted in two-fold resistance towards amicoumacin A. The fusA gene is known as the site for fusidic acid- resistant mutations; however the codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance occur in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.

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Inducible Costimulator Contributes to Methicillin-Resistant Staphylococcus aureus Pneumonia.

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