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Modulation of Heparan Sulfate Proteoglycans During Herpes Simplex Virus Type-1 Infection

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Title: Modulation of Heparan Sulfate Proteoglycans During Herpes Simplex Virus Type-1 Infection
Author(s): Karasneh, Ghadah A.
Advisor(s): Shukla, Deepak
Contributor(s): McLachlan, Alan; Chen, Zheng; Freitag, Nancy; Valyi-nagy, Tibor
Department / Program: Microbiology and Immunology
Graduate Major: Microbiology and Immunology
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): Herpes Simplex Virus Type-1 HSV-1 entry HSV-1 mediated cell-to-cell fusion HSV-1 cell-to-cell spread Heparan sulfate proteoglycan Syndecan Heparanase Glycoprotein Heparan Sulfate Syndecan shedding
Abstract: Herpes simplex virus type-1 (HSV-1) is an important human pathogen that relies heavily on cell-to-cell spread for establishing a lifelong latent infection. The result is a very successful prevalence of the virus in the human population infecting 40-80% of people worldwide. It causes oral and ocular lesions and more serious diseases, such as blindness, meningitis, and encephalitis. HSV-1 is a leading cause of viral corneal blindness and viral encephalitis in developed countries. HSV-1 entry into host cell is a multistep process that involves the interaction of the viral glycoproteins with various cell surface receptors. The role of heparan sulfate proteoglycans (HSPG) during HSV-1 infection has focused solely on the role of HS chains as an attachment receptor for the virus, while the core protein has been assumed to perform a passive role of only carrying the HS chains. Likewise, very little is known about the involvement of any specific HSPGs in HSV-1 lifecycle. The purpose of this study was to further analyze the contribution and modulation of HSPG during HSV-1 infection. Syndecan-1 is predominantly expressed in epithelial cells which are prime targets for HSV-1 initial infection. Therefore, this study is focused primarily on the contribution of this family member on HSV-1 infection. Important findings in this study include: (i) The core protein of syndecan-1 facilitates HSV-1 induced cell-to-cell fusion. CHO-745 cells, which are deficient in glycosaminoglycans’ (GAGs) synthesis including HS, were utilized to evaluate HS-independent contribution of syndecan-1 to cell fusion. (ii) Syndecan-1 facilitates HSV-1 cell-to-cell spread, as evident by determining HSV-1 plaque size, and utilizing a spread assay after changing syndecan-1 expression level on the cell surface through syndecan-1expression plasmid and syndecan-1 specific siRNA transfection. (iii) Modulating HSPG by Heparanase induces HSV-1 release from infected cells. Heparanase modulation was achieved by enhancing Heparanase expression, and by treating cells with exogenous recombinant Heparinases. (iv) HSV-1 infection induces active Heparanase expression, which is associated with a reduction in inactive Heparanase expression. Together, our study has expanded our understanding of HSPG role in HSV-1 infection, and has provided new insights into the modulation of HSPG during HSV-1 infection which might help the development of new antiviral agents or an effective HSV-1 vaccine.
Issue Date: 2012-12-10
Genre: thesis
Rights Information: Copyright 2012 Ghadah A. Karasneh
Date Available in INDIGO: 2012-12-10
Date Deposited: 2012-08

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