Date of Award

8-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Microbiology

Major Professor

Tim E. Sparer

Committee Members

Jeffrey M. Becker, Barry T. Rouse, Vitaly V. Ganusov

Abstract

Human Cytomegalovirus (HCMV) is the leading cause of both non-hereditary mental retardation and hearing loss, and CMV infection/reactivation causes serious complications in transplant and immune compromised patients. Due to these issues, development of a CMV vaccine and/or therapeutics is required. To achieve this goal, it is necessary to gain a better understanding of CMV pathogenesis. Because of its coevolution with humans, HCMV has evolved genes with homology to human immune modulatory genes. Several of these genes help CMV establish a successful and lifelong infection within the host. An example is the viral CXC chemokine homolog UL146 gene (vCXCL-1). UL146 varies between clinical isolates and has been associated with clinical outcomes of HCMV infection. In this dissertation we characterized the vCXCL-1 protein from different clinical isolates in vitro (chapter 1). We hypothesized that, variability in vCXCL-1 leads to differential activation of neutrophils, which in turn leads to the observed differences in HCMV pathogenesis. In this study we identified the similarities and differences in the functional activity of vCXCL-1 from different HCMV isolates and suggest how the variability can affect neutrophil function and CMV pathogenesis. In order to understand the contribution of vCXCL-1 in the pathogenesis of CMV infection in vivo (chapter 2), we tested the hypothesis that vCXCL-1 from chimpanzee CMV (vCXCL-1CCMV) is a functional CXC chemokine and contributes to viral dissemination, similar to MCMV CC chemokine. However, contrary to this hypothesis, we found that overexpression of the chemokine is detrimental to the dissemination of MCMV by recruiting more inflammatory monocytes and NK cells to the site of infection. In an effort to develop a novel anti-CMV treatment, we tested the hypothesis that heparan sulfate binding peptides can act as potential antivirals (chapter 3). Peptides of different lengths and net charge were generated and tested for their ability to prevent MCMV infections. Of those tested the cationic peptides reduced MCMV infection in vitro by ~ 90%. In summary my research suggests that over expression of chemokines can attenuate CMV dissemination making it a potential vaccine candidate and that a peptide that binds to heparan sulfate can be a potential CMV therapeutic.

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