Dissertation/Thesis Abstract

Autophagy, ROS and aging impact cytosolic antiviral immunity
by Tal, Michal Caspi, Ph.D., Yale University, 2012, 179; 3535395
Abstract (Summary)

In this thesis we show that pro-inflammatory cytokine production in response to viral ligands is increased in several situations: (1) in the absence of autophagy, (2) during increased oxidative stress, and (3) in the elderly. We find that autophagy is essential for maintaining the integrity of, and the appropriate amount of, mitochondria. Mitochondria serve as an integral platform whereby antiviral defense initiation pathways are coordinated with sensing of cellular stress, and thereby autophagy is critical for regulating the signaling emanating from the mitochondria. Accumulation of damaged mitochondria within a cell leads to increased mitochondrial reactive oxygen species production, and our studies show that this leads in increased cytosolic antiviral signaling and confers some protection from viral infection. Further, we find evidence for defective autophagy in human aging, as well as increased levels of mitochondrial ROS with age. We find this even in hematopoietic stem cells and throughout the progeny hematopoietic cells and we investigate the functional implications for the accumulation of damaged mitochondria and elevated levels of oxidative stress on the innate immune response to viral infection in the elderly. The implications of this study are that modulation of autophagy levels or the dysregulated pro-inflammatory cytokine production that results from defects in autophagy could possibly benefit the aging antiviral immune response.

Indexing (document details)
Advisor: Iwasaki, Akiko
Commitee: Medzhitov, Ruslan, Mothes, Walther, Shadel, Gerald
School: Yale University
Department: Immunobiology
School Location: United States -- Connecticut
Source: DAI-B 74/05(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Aging, Virology, Immunology
Keywords: Cytosolic antiviral immunity, Influenza, Innate immunity, Mitochondria, Reactive oxygen species, Viruses
Publication Number: 3535395
ISBN: 9781267856753
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