A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response

MBio
Ann E LinVictor Nizet

Abstract

The M1T1 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 GAS ΔspyA mutant 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 macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and ΔspyA GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar in vitro findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection. Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in h...Continue Reading

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Citations

Oct 27, 2015·Frontiers in Immunology·Christopher N LaRock, Victor Nizet
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Feb 16, 2019·Microbiology Spectrum·Vijay Pancholi
Jun 23, 2021·Cellular Microbiology·Johanna RichterMark J Walker

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Methods Mentioned

BETA
PCR
reverse
enzyme-linked immunosorbent assay
ELISA
transgenic
transfection
transfecting
ELISAs

Software Mentioned

Graph Pad Prism

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