Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Virus cell entry represents one of the earliest opportunities for a host to respond to infection. Understanding the processes of pathogen detection and restriction employed by the host, as well as strategies utilized by the virus itself to evade such processes, is critical in developing therapeutics to counter pathogenesis. Adenovirus (Ad) infections are self-limiting in healthy populations, but can be devastating to individuals with compromised immune systems. Currently, no specific antiviral treatments exist to combat Ad infections in susceptible populations. However, because Ad infections are not severe in healthy individuals, employing replication-defective Ads as vaccine vectors is generally regarded as safe, and as such are undergoing thorough investigation. The effects of Ads on human health, both from infection and as a vaccine vector, are substantial; however there are still informational gaps when describing the virus’ interactions within host cells to produce an infection. Furthermore, viruses manipulate specific pathways to ensure they productively replicate and produce progeny virions, making them ideal tools to probe such complex host pathways.

Our lab uses Ad to investigate both mechanisms of host-mediated restriction of virus and the pathogen’s methods of evading detection. Understanding the contributions of distinct mechanisms employed by Ad to evade host responses and efficiently enter cells will enhance the efficacy of future Ad vaccine vectors and identify novel targets for antiviral drug developments. Previous studies in our lab show that Ad-induced membrane rupture stimulates a host cell response characterized by the recruitment of autophagy machinery to sites of damage. Other observations suggest that wild-type Ad5 virions evade sequestration by autophagy via the recruitment and engagement of microtubule motor proteins. Current studies suggest that multiple viral proteins making up the viral capsid function to aid in motor protein recruitment and viral transport throughout the cell, but the specific details of these molecular interactions have not been entirely discerned. This study examines the mechanisms of autophagy induction by the host during Ad entry, and assesses the influences of capsid proteins of virion engagement with microtubules to facilitate endosomal egress and translocation to the nucleus.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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