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Group A Streptococcus Induces Caspase‐independent IL‐1 Signaling
Author(s) -
LaRock Christopher,
Todd Jordan,
Olson Joshua,
Hoffman Hal,
Nizet Victor
Publication year - 2015
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.29.1_supplement.770.3
Subject(s) - pyroptosis , caspase 1 , protease , virulence factor , virulence , signal transduction , caspase , microbiology and biotechnology , immune system , proteases , cytokine , immunology , biology , chemistry , apoptosis , programmed cell death , inflammation , enzyme , inflammasome , biochemistry , gene
Pro‐inflammatory signaling through the IL‐1 pathway is essential for controlling Group A Streptoccocus (GAS) infection. IL‐1b is post‐translationally regulated by caspase‐1, a protease that hydrolyzes the immature cytokine into it's biologically active form. This pathway is aberrantly induced in autoinflammatory diseases, but is critical in controlling infection when properly controlled, so pathogens typically work to evade this hyper‐inflammatory pathway. However, GAS highly activates IL‐1 signaling, even in the absence of it's essential regulator caspase‐1. Using mutant bacteria, knockout mice, and pharmacological inhibitors of caspase‐1 and IL‐1, we describe IL‐1 activation by the bacterial protease SpeB. SpeB acts as a bacterial caspase, stimulating not only IL‐1, but also other caspase‐1‐regulated pathways including a distinct program of cell death termed pyroptosis. SpeB is a critical virulence factor that inactivates immune components including antibodies, antimicrobial peptides, complement, and cytokines. Therefore, SpeB‐mediated virulence is at the expense IL‐1 activation. Invasive infection correlates with mutants no longer expressing SpeB, suggesting that IL‐1 is a primary barrier to serious disease. Pharmacological inhibition of IL‐1 signaling and caspase‐1 can help treat autoinflammatory disease; this increases infection rates in general, but severe GAS infection in particular. These findings may therefore provide a mechanistic explanation for the increased virulence of GAS in these patients.