Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Susan R. Weiss

Abstract

Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is protective during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response.

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