Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

David Artis

Abstract

Alterations in the composition of commensal bacterial communities in the human intestine are associated with enhanced susceptibility to multiple inflammatory diseases. Further, studies in murine model systems have demonstrated that signals derived from commensal bacteria can influence immune cell development, function and homeostatic regulation within the intestinal environment, leading to altered host susceptibility to infectious or inflammatory diseases. However, whether commensal bacteria-derived signals regulate protective immunity to viral pathogens that infect sites outside of the gastrointestinal microenvironment remain poorly understood. Chapter 2 of this thesis examines this question and demonstrates that disruption or absence of commensal bacterial communities results in impaired protective immunity to respiratory influenza virus. Antibiotic (ABX)-mediated disruption of intestinal commensal bacteria significantly impaired the innate and adaptive immune response, abrogated viral clearance and increased host mortality following influenza virus infection indicating a crucial role for commensal bacterial communities in regulating antiviral immune defense. Chapter 3 interrogates the influence of commensal bacteria-derived signals on the antiviral immune response to systemic viral infection. Following infection with Lymphocytic Choriomeningitis virus (LCMV), ABX-treated mice exhibited functionally impaired LCMV-specific CD4 and CD8 T cell responses that correlated with significantly delayed viral clearance. Collectively, Chapters 2 and 3 indicate a global role for commensal bacteria-derived signals in regulating immunity to mucosal or systemic viral infection. Chapter 4 examines the mechanisms underlying commensal bacteria regulation of antiviral immunity and identifies a previously unrecognized role for commensal bacteria-derived signals in establishing the activation threshold of the innate immune system. Genome-wide transcriptional profiling of macrophages isolated from ABX-treated mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages isolated from ABX-treated mice prior to viral infection exhibited defective responses to type I/II IFNs and a reduced capacity to limit viral replication. Strikingly, adoptive transfer of macrophages from CNV mice into ABX-treated mice prior to LCMV infection resulted in significantly improved virus-specific adaptive immune responses and effectively restored the ability of ABX-treated mice to control viremia. Taken together, the results presented in this thesis indicate that commensal bacteria-derived signals calibrate the activation threshold of the innate immune system, providing tonic immune stimulation essential for optimal antiviral immunity.

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