Staphylococcus aureus Evades Lysozyme-Based Peptidoglycan Digestion that Links Phagocytosis, Inflammasome Activation, and IL-1β Secretion

Abstract

Summary IL-1β produced by phagocytes is important for protection against Staphylococcus aureus. Secretion of this cytokine requires both activation of a transcriptional signal to stimulate production of pro-IL-1β, and a second signal to stimulate processing by inflammasome complexes and release of the mature cytokine. We show here that phagocytosis and lysozyme-based degradation of bacterial cell walls are functionally coupled to activation of NLRP3 inflammasomes and secretion of IL-1β in response to live S. aureus and to S. aureus peptidoglycan. Further a S. aureus enzyme, peptidoglycan O-acetyl transferase A, previously demonstrated to make cell wall peptidoglycan resistant to lysozyme strongly suppresses inflammasome activation and inflammation in vitro and in vivo. This is the first demonstration of a case whereby a bacterium specifically subverts IL-1β secretion through chemical modification of its cell wall peptidoglycan.

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA–Mediated Host Killing in the Airways

“…Nonetheless, S. aureus adenosine may regulate other inflammatory mediators. Indeed, recent works highlighted the essential role of phagocytosis and PGN/NOD2 in IL-1b secretion (39,47), a key inflammatory cytokine in the host response to S. aureus (48). In this work, we showed that adenosine decreased S. aureus phagocytosis through A2aR (Fig.…”

“…2E). Indeed, engulfed bacteria are known to be degraded into phagolysosomes and to release PGN (39). The latter is sensed by the cytoplasmic receptor NOD2 (6).…”

Downregulation of the Na/K-ATPase Pump by Leptospiral Glycolipoprotein Activates the NLRP3 Inflammasome

“…We therefore used hexachitohexaose, a lysozyme inhibitor, to check if leptospiral PG could be involved. As expected (24), the induction of IL-1b secretion by PG from S. aureus was inhibited by the lysozyme inhibitor, although no effect was observed on IL1b secretion after L. interrogans infection (Fig. 2C).…”

“…In addition, recent work showed that the degradation of S. aureus PG by lysozyme in lysosomes was able to trigger IL-1b production (24). We therefore used hexachitohexaose, a lysozyme inhibitor, to check if leptospiral PG could be involved.…”

NOD2 Stimulation by Staphylococcus aureus-Derived Peptidoglycan Is Boosted by Toll-Like Receptor 2 Costimulation with Lipoproteins in Dendritic Cells

“…This modification, which occurs only in pathogenic staphylococcal strains (18), confers complete resistance of PGN to lysozyme, while mutations of the oatA gene result in a PGN that is sensitive to lysozyme (17,19). In comparing PGNpol from WT S. aureus with PGN from the oatA-deficient mutant (S. aureus ⌬oatA), it turned out that WT PGNpol strongly suppressed interleukin-1␤ (IL-1␤) secretion and inflammasome activation, while the PGNpol of the S. aureus ⌬oatA strain strongly increased IL-1␤ secretion and inflammasome activation (20). In the absence of oatA, PGN is degraded by lysozyme, resulting in a number of PGN breakdown products which boost inflammation.…”