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

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. [Display omitted] •PBP2A induction in MRSA leads to hyper-inflammatory peptidoglycan (PGN)•PBP2A-made PGN is poorly cross-linked and strongly activates the NLRP3 inflammasome•Genetic alteration resulting in reduced S. aureus PGN cross-links induces inflammation•Induction of PBP2A by β-lactam antibiotics heightens MRSA pathogenicity in vivo Methicillin-resistant Staphylococcus aureus infection is associated with a worse outcome. Müller et al. demonstrate that the enzyme that confers resistance to methicillin, PBP2A, enhances immunopathology associated with MRSA infection. PBP2A produces poorly cross-linked peptidoglycan, which strongly activates the NLRP3 inflammasome and drives release of high amounts of IL-1β.