Caspase-8, RIPK1 and FADD regulate cell death and caspase-1 activation during yersinia infection (INM3P.438)

Abstract

Abstract Programmed cell death is an evolutionarily conserved response to infection that can promote host defense or microbial virulence. Pathogens manipulate various immune signaling pathways through the activity of specific virulence factors that access the host cell cytosol. Cell death is a major consequence of infection with pathogenic Y. pseudotuberculosis and requires the effector YopJ, a potent inhibitor of NF-κB and MAPK signaling. However, the pathways that regulate cell death in response to Yersinia infection and the precise mechanism by which cell death mediates protective immunity are not well understood. We find a novel requirement for caspase-8, receptor interacting protein 1 (RIPK1) and Fas-associated protein with death domain (FADD) in Yersinia-induced cell death and pro-inflammatory caspase-1 activation. Moreover, mice deficient in caspase-8 were highly susceptible to Yersinia infection and were unable to sustain innate cytokine production. We hypothesize that activation of these pathways during Yersinia infection may induce specific pro-inflammatory signals that shape innate and adaptive responses and promote microbial clearance.