Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Igor E. Brodsky

Abstract

Many pathogens interfere with the activation of innate immune signaling responses. However, pro-survival and cell death-inducing signals are coupled downstream of innate immune receptors, such that survival signals prevent cell death in the context of inflammatory stimuli. Blockade of key signaling pathways by pathogen virulence factors uncouples this coordinate regulation, resulting in activation of programed cell death. Thus, cell death may act as a conserved host protective mechanism for inducing inflammation in response to pathogens that interfere with immune signaling pathways. The YopJ virulence factor of the gram-negative bacterial pathogen Yersinia pseudotuberculosis potently inhibits NF-κB and MAPK signaling, resulting in death of infected innate immune cells. This cell death occurs through a pathway involving caspase-8 and receptor-interacting serine/threonine kinase 1 (RIPK1) downstream of toll-like receptor 4 (TLR4) and TIR-domain-containing adapter-inducing interferon-β (TRIF). Our studies reveal that TNFR1 signaling additionally acts to promote Yersinia-induced cell death, via caspase-8 and RIPK1. Importantly, cell-extrinsic TNF, produced by cells that escape the effects of YopJ inhibition, is necessary for promoting this response. Thus, innate immune cytokine signaling acts to potentiate the apoptotic response to pathogen inhibition and perhaps reflects a coordinated response by heterogeneous cell populations to counter infection. We further demonstrate an in vivo function for RIPK1 kinase activity in promoting host protection and inflammatory cytokine responses to Yersinia infection that is consistent with a function of Yersinia-induced apoptosis in promoting host protective anti-bacterial immunity. Together, these data demonstrate that the apoptotic response induced during infection with pathogens that inhibit host signaling is promoted by cytokine signaling and plays an important role in potentiating host protection. Understanding the regulation of these responses to infection provides novel mechanistic insight into the pathways that may regulate cell death and inflammation in diverse pathologic states and could be targeted to treat disease.

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