GSBS Dissertations and Theses

Approval Date

3-30-2015

Document Type

Doctoral Dissertation

Academic Program

Immunology and Microbiology

Department

Medicine

First Thesis Advisor

Katherine A. Fitzgerald, PhD

Keywords

Influenza A virus, Innate Immunity, Inflammasones, Nucleic Acids

Subjects

Dissertations, UMMS; Influenza A virus; Immunity, Innate; Inflammasones; Nucleic Acids

Abstract

Innate sensing of nucleic acids lies at the heart of antiviral host defense. However, aberrant activation of innate sensors by host nucleic acids can also lead to the development of autoimmune diseases. Such host nucleic acids can also be released from stressed, damaged or dying cells into the tissue microenvironment. It however remains unclear how the extracellular nucleic acids impacts the quality of the host immune responses against viral infections. Using a mouse model of influenza A virus (IAV) infection, we uncovered an important immune-regulatory pathway that tempers the intensity of the host-response to infection. We found that host-derived DNA from necrotic cells accumulates in the lung microenvironment during IAV infection, and is sensed by the DNA receptor Absent in Melanoma 2 (AIM2). AIM2-deficiency resulted in severe immune pathology highlighted by enhanced recruitments of immune cells, and excessive systemic inflammation after IAV challenge, which led to increased morbidity and lethality in IAV-infected mice. Interestingly, these effects of AIM2 were largely independent of its ability to mediate IL-1β maturation through inflammasome complexes. Finally, ablation of accumulated DNA in the lung by transgenic expression of DNaseI in vivo had similar effects. Collectively, our results identify a novel mechanism of cross talk between PRR pathways, where sensing of hostderived nucleic acids limits immune mediated damage to virus infected tissues.

DOI

10.13028/M2H88K

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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