Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Marco Colonna

Abstract

The innate immune system consists of a number of genetically encoded receptors that detect the products of viral replication and initiate signaling cascades leading to activation of the antiviral response. During the course of infection, many viruses produce dsRNA that can be recognized by two major arms of the innate immune system: the toll-like receptors: TLR) and the Rig-I-like receptors: RLR). Among the TLRs, TLR3 binds dsRNA within the endosomal compartment and initiates signaling through its downstream adapter TRIF. Melanoma differentiation-induced gene 5: MDA5) is a member of the RLR family that recognizes dsRNA within the cytosolic compartment and signals through the adaptor IPS-1. Although TLR3 and MDA5 initially employ distinct downstream adaptors, both are known to induce the production of cytokines and cell surface molecules involved in the antiviral response, which raises the question of whether they are redundant or functionally distinct. Using mice that are genetically deficient for MDA5, TLR3, or both MDA5 and TLR3: double knockout, DKO), we have demonstrated that these receptors have unique functions necessary for controlling viral infection. Using two models of viral infection, murine norovirus: MNV) and encephalomyocarditis virus: EMCV), we demonstrate that both MDA5 and TLR3 limit viral replication. Neither MDA5-/- nor TLR3-/- animals controlled MNV and EMCV infection as well as wild type: WT) controls, but DKO mice were more susceptible to infection than either single knockout. Furthermore, we find that MDA5 and TLR3 play distinct roles in activating the natural killer: NK) cell response to the dsRNA analogue poly I:C: pIC). We demonstrate that the discrete functions of MDA5 and TLR3 are dependent on their expression in different cell types as well as their unique capacities to control production of cytokines. In addition, we show that the individual contribution of each sensor is necessary at distinct phases of the innate immune response, with TLR3 acting initially and MDA5 acting at later time points. These results illustrate how cooperation between the TLR and RLR pathways is necessary for the development of a complete antiviral response.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7G73BQP

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