A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1-Dependent Macrophage Immune Response

ABSTRACT TheM1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the covRS regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GASspyAmutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macro-phage cell death in association with caspase-1-dependent interleukin 1 (IL-1) production, and differences between wild-type (WT) andspyAGASmacrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1. Similar in vitro findings were identified in macrophage studies per-formed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1-dependent innate immune response pathway critical in defense against invasive bacterial infection. IMPORTANCE Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosyla-tion. We describe howmacrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1 (IL-1). Release of IL-1 activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophag