Dissertation Defense Announcement
To: The George Mason University Community
Candidate: Lindsay Lundberg
Program: PhD in Biosciences
Date: Thursday March 22, 2018
Time: 10:00 AM
Place: George Mason University
Science & Tech Campus
Institute for Advanced Biomedical Research, Room 1004
Title: "Venezuelan Equine Encephalitis Virus Capsid and Host Nucleocytoplasmic Trafficking"
Dr. Kylene Kehn-Hall
Committee Members: Dr. Aarthi Narayanan, Dr. Mikell Paige, Dr. Yuntao Wu
This is a public defense and all are invited to attend.
Venezuelan equine encephalitis virus (VEEV) is endemic to South, Central, and North America and causes an acute, febrile-like illness in humans that occasionally progresses to neurological involvement and rarely death. There are no FDA-approved therapeutics or vaccines for human use. It was weaponized by both the US and USSR and is considered a Category B Select Agent by the CDC. Thus, it is imperative to understand the interactions between host and viral proteins to develop targeted therapeutics that modulate host responses. VEEV capsid is known to directly interact with the host export protein, CRM1, and the import proteins, importin á/â1, forming a tetrameric complex that halts nucleocytoplasmic trafficking, downregulates host transcription, and alters the cell cycle. It is hypothesized that interfering with this interaction will reduce viral titers and pathogenesis and restore dysregulated cell functions by segregating capsid during viral assembly, freeing the nuclear pore to transport cellular factors that will help counter infection and promote cell survival. To that end, in silico and in vitro compound screens were performed to identify novel inhibitors of importin á and capsid, yielding new scaffolds for further research. The importin á inhibitor mifepristone was chemically modified, producing additional compounds to test for antiviral efficacy. Novel inhibitors of export, specifically CRM1, were also tested for antiviral efficacy but failed to protect mice in an infection model. Finally, the infection induced delay in G1 of the cell cycle was traced to VEEV capsid, and the cell cycle aberration was confirmed on both the protein and RNA levels. This body of work demonstrates multiple novel chemical scaffolds targeting VEEV capsid which have the potential for further antiviral drug development.