Oral Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

Group A Streptococcal M protein activates the NLRP3 inflammasome and triggers programmed cell death in macrophages (#88)

Andrés Valderrama 1 , Angelica Riestra 1 , Nina Gao 1 , Christopher LaRock 1 , Naveen Gupta 1 , Partho Ghosh 2 , Victor Nizet 1
  1. Division of Host-Microbe Systems & Therapeutics, University of California San Diego, La Jolla, California, United States
  2. Chemistry and Biochemistry , University of California San Diego, La Jolla, California, United States

Group A Streptococcus (GAS) is among the top 10 causes of infection-related mortality in humans. M protein, the most abundant protein on the GAS surface, is one of the best studied of all Gram-positive bacterial virulence factors. M protein extends from the GAS surface as hair-like fimbriae, and its structure, function, and immunochemistry are unique among known virulence molecules. M1 serotype GAS strains are associated with invasive infections including necrotizing fasciitis and toxic shock syndrome. M proteins, including M1, can be released during infection by the action of neutrophil-derived granule proteases. Under physiological conditions, M1 protein is also naturally released from the GAS surface and can be detected at high concentrations in the extracellular medium. Here we report a novel property of released, soluble M1 protein in triggering programmed cell death in macrophages. M1 served as a second signal for caspase‑1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine IL‑1β and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 is critical for inflammasome activation, which involves K+ efflux and M1 protein internalization by clathrin-mediated endocytosis. Comparisons in the production of IL-1β during infection in vivo between GAS and GASΔM1-infected mice demonstrated that when M1 is present, the production of IL-1β is higher. Accordingly, mouse intraperitoneal challenge showed that GAS soluble M1 is sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1‑mediated pyroptosis and IL-1β release could aggravate tissue injury.