title: Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology.
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.
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Müller
authors.affiliation: Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wolf
authors.affiliation: Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Iliyan D
authors.initials: ID
authors.lastname: Iliev
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Berg
authors.affiliation: Division of Biomedical Sciences and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: david.underhill@csmc.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Underhill
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: george.liu@cshs.org.
authors.forename: George Y
authors.initials: GY
authors.lastname: Liu
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007769:Lactams / Q000627:therapeutic use; D055624:Methicillin-Resistant Staphylococcus aureus / Q000472:pathogenicity* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D007769:Lactams; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; C487789:mecA protein, Staphylococcus aureus