Dissertations, Theses, and Capstone Projects

Date of Degree

2011

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Zahra Zakeri

Committee Members

Stephane Boissinot

Patricia Rockwell

Richard Lockshin

Adolfo Garcia-Sastre

Subject Categories

Biology

Abstract

Viruses employ a variety of strategies to manipulate cell fate and maximize their replication potential during infection. Interacting specifically with cell death pathways allows viruses direct control over the cellular decision to survive or die during infection.

Influenza A virus, of the family Orthomyxoviridae, encodes proteins that interact with the cell at several points along the apoptosis pathway to induce apoptosis. We demonstrate that caspase activation through pro-apoptotic Bax, a downstream target of Bcl-2, is a critical determinant of the nature of cell death induced by Influenza A infection. Influenza A virus cannot establish an apoptotic response without functional Bax, and instead elicits autophagy after infection. Efficient virus replication is dependent upon Bax-mediated apoptosis as Bax KO also causes a 99% reduction in Influenza A viral titer.

In stark contrast, cells infected with Dengue-2 or Modoc virus of the family Flaviviridae do not die, even at high MOI. Instead, infection with either of these flaviviruses generates an autophagy-dependent protection against several toxins. Autophagy upregulation following infection is also critical to maximum flavivirus replication. Expression of NS4A from either virus is uniquely sufficient to elicit both autophagy and protection against death similar to whole virus infection. As autophagy upregulation is essential for maximum flavivirus replication, flavivirus NS4A is therefore identified as a potential target for the development of specific anti-viral therapy for flavivirus infection.

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