Certain cancers occur as a consequence of infections with particular herpesviruses. In addition, most people become infected with one or more herpesviruses, which can persist indefinitely in quiescent state but then reactivate in immunosuppressed individuals, including cancer patients, to cause significant disease. The studies described here are directed toward understanding basic mechanisms that are central to herpesvirus infection of cells and spread from cell-to-cell, namely the mechanisms of herpesvirus-induced membrane fusion. Herpesvirus entry into cells requires fusion of the outer envelope of the virus with a cell membrane. Spread of infection can occur via infectious virus or virus-induced cell fusion. The ultimate objective of studies described here is to understand how herpesviruses, specifically herpes simplex viruses (HSV), induce membrane fusion, the process required for viral entry and cell fusion. Requirements for HSV-induced membrane fusion include the coordinated activities of four HSV glycoproteins (gB, gD, gH and gl_)and interaction of gD with a cell surface receptor such as nectin-1. Our hypothesis is that binding of gD, present in the viral envelope or an infected cell surface, to a gD receptor on an uninfected cell somehow activates the fusogenic activity of gB and/or gH-gL (a heterodimeric complex). This activation could result from the physical interaction of gD (altered by its binding to receptor) with gB or gH-gL or both. Alternatively, the gD- receptor interaction could activate gB or gH-gL by some indirect transmission of a signal.
The specific aims are (1) to define the sequence requirements for a region of gD that is required for cell fusion, but not for receptor binding;(2) to identify regions of gB and gH that are essential for membrane fusion, through random mutagenesis and cell fusion assays;(3) to define conditions or mutations in gB that permit cell fusion to be induced by gB in the absence of gD and/or gH-gL;(4) to identify protein complexesthat contain gD plus one or more of the other viral glycoproteins, that are induced in response to gD-receptor interaction and that fail to form when either gD or one of the other glycoproteins is non-functional for membrane fusion. The results of these studies, combined with structural studies in progress in other laboratories, will lead to an understanding of the mechanism(s) of herpesvirus-induced membrane fusion and to new approaches for the prevention and treatment of herpesvirus infections and disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA021776-33
Application #
7774354
Study Section
Virology - B Study Section (VIRB)
Program Officer
Daschner, Phillip J
Project Start
1977-09-01
Project End
2013-01-31
Budget Start
2010-03-01
Budget End
2013-01-31
Support Year
33
Fiscal Year
2010
Total Cost
$261,514
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Fan, Qing; Kopp, Sarah; Connolly, Sarah A et al. (2017) Mapping sites of herpes simplex virus type 1 glycoprotein D that permit insertions and impact gD and gB receptors usage. Sci Rep 7:43712
Edwards, Rebecca G; Longnecker, Richard (2017) Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye. J Virol 91:
Wilcox, Douglas R; Longnecker, Richard (2016) The Herpes Simplex Virus Neurovirulence Factor ?34.5: Revealing Virus-Host Interactions. PLoS Pathog 12:e1005449
Wilcox, Douglas R; Folmsbee, Stephen S; Muller, William J et al. (2016) The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis. MBio 7:e00437-16
Wilcox, Douglas R; Muller, William J; Longnecker, Richard (2015) HSV targeting of the host phosphatase PP1? is required for disseminated disease in the neonate and contributes to pathogenesis in the brain. Proc Natl Acad Sci U S A 112:E6937-44
Wilcox, Douglas R; Wadhwani, Nitin R; Longnecker, Richard et al. (2015) Differential reliance on autophagy for protection from HSV encephalitis between newborns and adults. PLoS Pathog 11:e1004580
Lajko, Michelle; Haddad, Alexander F; Robinson, Carolyn A et al. (2015) Using proximity biotinylation to detect herpesvirus entry glycoprotein interactions: Limitations for integral membrane glycoproteins. J Virol Methods 221:81-9
Fan, Qing; Longnecker, Richard; Connolly, Sarah A (2015) A Functional Interaction between Herpes Simplex Virus 1 Glycoprotein gH/gL Domains I and II and gD Is Defined by Using Alphaherpesvirus gH and gL Chimeras. J Virol 89:7159-69
Edwards, Rebecca G; Kopp, Sarah J; Karaba, Andrew H et al. (2015) Herpesvirus entry mediator on radiation-resistant cell lineages promotes ocular herpes simplex virus 1 pathogenesis in an entry-independent manner. MBio 6:e01532-15
Fan, Qing; Longnecker, Richard; Connolly, Sarah A (2014) Substitution of herpes simplex virus 1 entry glycoproteins with those of saimiriine herpesvirus 1 reveals a gD-gH/gL functional interaction and a region within the gD profusion domain that is critical for fusion. J Virol 88:6470-82

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