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Paring down pyroptosis
Shiga toxin is a phage-encoded exotoxin that interrupts protein translation and functions as a virulence factor for enterohemorrhagic Escherichia coli (EHEC), a human pathogen causing hemorrhagic colitis and acute renal failure. Havira et al. screened a panel of EHEC mutants lacking various virulence factors for mutants that interfered with inflammasome-mediated cell death. EHEC strains lacking Shiga toxin were more potent inducers of macrophage pyroptosis and IL-1β secretion than wild-type EHEC. Shiga toxin from wild-type EHEC interfered with pyroptosis by blocking the ability of the activated form of caspase-11, a cytoplasmic LPS sensor, to cleave gasdermin D and initiate formation of gasdermin pores in the plasma membrane. This unanticipated activity of Shiga toxin provides EHEC with an additional means of evading the innate immune system.
Abstract
Inflammatory caspase–dependent cytosolic lipopolysaccharide (LPS) sensing is a critical arm of host defense against bacteria. How pathogens overcome this pathway to establish infections is largely unknown. Enterohemorrhagic Escherichia coli (EHEC) is a clinically important human pathogen causing hemorrhagic colitis and hemolytic uremic syndrome. We found that a bacteriophage-encoded virulence factor of EHEC, Shiga toxin (Stx), suppresses caspase-11–mediated activation of the cytosolic LPS sensing pathway. Stx was essential and sufficient to inhibit pyroptosis and interleukin-1 (IL-1) responses elicited specifically by cytosolic LPS. The catalytic activity of Stx was necessary for suppression of inflammasome responses. Stx impairment of inflammasome responses to cytosolic LPS occurs at the level of gasdermin D activation. Stx also suppresses inflammasome responses in vivo after LPS challenge and bacterial infection. Overall, this study assigns a previously undescribed inflammasome-subversive function to a well-known bacterial toxin, Stx, and reveals a new phage protein-based pathogen blockade of cytosolic immune surveillance.
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