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.

IL-1β produced by phagocytes is important for protection against Staphylococcus aureus, a bacterium that causes serious skin and invasive diseases and is contributing to a current public health crisis due to the emergence of methicillin-resistant strains. Secretion of IL-1β requires both activation of a transcriptional signal to stimulate production of pro- IL-1β, (usually provided by TLR signaling) 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 Nalp3 inflammasomes and secretion of IL-1β in response to live S. aureus and to S. aureus peptidoglycan. Further, a S. aureus peptidoglycan-modifying enzyme that makes its peptidoglycan resistant to lysozyme strongly suppresses inflammasome activation. This is the first demonstration of a case whereby a bacterium avoids IL-1β secretion through chemical modification of its cell wall peptidoglycan, and we hypothesize that this reduced IL-1β production is key to successful mucosal colonization and infection. This research is supported by grants from NIGMS and the American Heart Association.