Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Cathy King Madsen

Program: PhD in Biosciences



Date:   Tuesday July 14, 2015

Time:   10:00 am

Place:  George Mason University
             Science & Tech (Prince William) Campus<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>

             Occoquan Bldg., Room 110-L



Title: "Dependence of Two Arboviruses on the Host MicroRNA Pathway"
Committee Chair: Dr. Kylene Kehn-Hall
Committee Members:  Dr. Fatah Kashanchi, Dr. Barney Bishop, Dr. Norman Lee
A copy of the dissertation is available in the Mercer Library.  All are invited to attend the defense.
ABSTRACT:
Rift Valley fever virus (RVFV) and Venezuelan equine encephalitis virus (VEEV) are two mosquito-borne, select agent viruses with severe effects on humans and livestock, and for which no FDA-approved vaccines or specific treatments exist.  To identify potential therapeutic targets, this research focuses on viral interactions with host microRNA (miRNA), a class of small, non-coding RNA which bind to messenger RNA (mRNA) to regulate its endpoint proteins.  This study demonstrates dependence of both RVFV and VEEV on the host miRNA pathway through different means.  RVFV infection induces upregulation of miR-630 and miR-99a, which downregulate the anti-apoptotic protein IGF1R.  Inhibition of these miRNA partially rescues IGF1R and decreases viral replication.  Conversely, RVFV NSs protein inhibits the anti-apoptotic miR-17-92 cluster, revealing interplay between NSs and miRNA for control of host functions during infection, while overexpression of this cluster reduces viral replication.  In contrast, VEEV replication depends heavily on miRNA processing enzymes including Drosha, Exportin 5, and Argonaute 2 (Ago2).  Knockdown or inhibition of these enzymes leads to decreased replication and production of viral proteins. The Ago2 inhibitor acriflavine (ACF) reduces VEEV replication in both vaccine and virulent strains by approximately 6-log10 in culture, and is similarly effective against Eastern and Western equine encephalitis viruses.  Taken together, these data show the importance of the miRNA pathway for several types of virus, suggesting a fine-tuning function for replication in RVFV and an active use of the pathway itself for VEEV and related Alphaviruses.
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