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Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology.

TitlePoorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology.
Publication TypeJournal Article
Year of Publication2015
AuthorsMüller S, Wolf AJ, Iliev ID, Berg BL, Underhill DM, Liu GY
JournalCell Host Microbe
Volume18
Issue5
Pagination604-12
Date Published2015 Nov 11
ISSN1934-6069
Abstract

Methicillin-resistant S. aureus (MRSA) is a leading health problem. Compared to methicillin-sensitive S. aureus, MRSA infections are associated with greater morbidity and mortality, but the mechanisms underlying MRSA pathogenicity are unclear. Here we show that the protein conferring β-lactam antibiotic resistance, penicillin-binding protein 2A (encoded by the mecA gene), directly contributes to pathogenicity during MRSA infection. MecA induction leads to a reduction in peptidoglycan cross-linking that allows for enhanced degradation and detection by phagocytes, resulting in robust IL-1β production. Peptidoglycan isolated from β-lactam-challenged MRSA strongly induces the NLRP3 inflammasome in macrophages, but these effects are lost upon peptidoglycan solubilization. Mutant MRSA bacteria with naturally occurring reduced peptidoglycan cross-links induce high IL-1β levels in vitro and cause increased pathology in vivo. β-lactam treatment of MRSA skin infection exacerbates immunopathology, which is IL-1 dependent. Thus, antibiotic-induced expression of mecA during MRSA skin infection contributes to immunopathology by altering peptidoglycan structure.

DOI10.1016/j.chom.2015.10.011
Alternate JournalCell Host Microbe
PubMed ID26567511
PubMed Central IDPMC4648675
Grant ListDK098310 / DK / NIDDK NIH HHS / United States
R01GM085796 / GM / NIGMS NIH HHS / United States
R21 AI097741 / AI / NIAID NIH HHS / United States
R21AI097741 / AI / NIAID NIH HHS / United States