Date of Award

6-2013

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Karim Essani

Second Advisor

Dr. Bruce Bejcek

Third Advisor

Dr. Robert Eversole

Fourth Advisor

Dr. Chris Fisher

Keywords

Tanapox virus, epidermal growth factor, neuregulin, ErbB, heparin binding, oncolytic virus

Abstract

Studies on large dsDNA viruses such as poxviruses have been helpful in identifying a number of viral and cellular growth factors that contribute to our broad understanding of virus-host interaction. Orthopoxviruses and leporipoxviruses are among the most studied viruses in this aspect. However, tanapoxvirus (TPV) a member of the genus Yatapoxvirus, still remains largely unexplored, as the only known hosts for this virus are humans and monkeys. Here, we describe the initial characterization of an EGF-like growth factor mimicking human neuregulin from TPV, expressed by the TPV-15L gene. Assays using a baculovirus expressed and tagged TPV-15L protein demonstrated the ability to phosphorylate neuregulin receptors. Neuregulins represent a large family of EGF-like growth factors that play important roles in embryonic endocardium development, Schwann and oligodendrocyte survival and differentiation, acetylcholine receptor localization at the neuromuscular junction and epithelial morphogenesis. Interestingly, certain neuregulin molecules are able to target specific tissues through interactions with heparin sulfate proteoglycans via an immunoglobulin (Ig)-like domain. Analyses of TPV-15L revealed no Ig-like domain, yet it retains the ability to bind heparin and phosphorylate neuregulin receptors, providing compelling evidence that TPV-15L is a functional mimetic of neuregulin. TPV-15L knockout virus experiments demonstrate that the virus replicates in human umbilical vein endothelial cells less efficiently compared to wild type TPV-Kenya, indicating that it is non-essential for virus viability but can promote replication in some cultured cells. However, the precise role of this protein in host-virus interaction still remains to be determined.

Access Setting

Dissertation-Open Access

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