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Stimulation of inflammasome‐dependent innate response by group A streptococcus ADP‐ribosyltransferase protects host from bacterial infections (539.9)
Author(s) -
Lin Ann,
Beasley Federico,
Keller Nadia,
Hoffman Harold,
Nizet Victor
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.539.9
Subject(s) - inflammasome , streptococcus pyogenes , microbiology and biotechnology , pyroptosis , innate immune system , biology , macrophage , caspase 1 , immunology , staphylococcus aureus , immune system , inflammation , bacteria , in vitro , biochemistry , genetics
Streptococcus pyogenes (GAS) is a causative agent of severe invasive infections including necrotizing fasciitis, bacteremia and toxic shock syndrome. SpyA (S. pyogenes ADP‐ribosyltransferase) is one of a subset of virulence factors significantly up‐regulated in the hyper‐invasive strain of a globally disseminated M1T1 GAS. Surprisingly, mice systematically challenged with GAS ΔspyA suffered significantly higher mortality and displayed reduced bacterial clearance. We recovered higher levels of ΔspyA GAS compared to the wild‐type (WT) strain from bone marrow‐derived macrophage (BMDM) killing assays. Complementation of the GAS ΔspyA mutant restored the WT BMDM survival phenotype, heterologous expression of SpyA in Staphylococcus aureus or the macrophage itself led to a significant increase in bacterial killing. Increased bacterial survival of the ΔspyA mutant was associated with severe attenuation of caspase‐1 dependent inflammasome activation and impaired IL‐1β production. BMDMs deficient in caspase‐1, NLRP3, ASC or pro‐ IL‐1β reversed the effect of SpyA expression on macrophage survival and abolished protection seen in WT infected mice. In conclusion, SpyA triggers caspase‐1 dependent inflammatory responses, or “pyroptosis” in macrophages, highlighting the importance of this macrophage innate immune response pathway in defense against invasive bacterial pathogens. Grant Funding Source : Canadian Institutes of Health Research (CIHR)