Perelman School of Medicine at the University of Pennsylvania

Penn Institute for Immunology

Claude F Krummenacher

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Contact information
University of Pennsylvania
School of Veterinary Medicine
Department of Pathobiology
Rosenthal Bldg 412
3800 Spruce St.
Philadelphia, PA 19104
Office: 215 573 8567
Fax: 215 898 37887
BS (Biology)
University of Lausanne, Switzerland, 1990.
PhD (Virology)
University of Lausanne, Switzerland, 1995.
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Description of Research Expertise

Research interests: My lab is interested in the role of nectins as receptors during entry of herpes simplex virus and as adhesion molecules located at intercellular junctions.

Keywords: HSV, herpes simplex virus, nectins, receptors, virus entry cell adhesion, adherens junctions, protein structure.

Research details:My studies focus on the nectins, a family of cell adhesion molecules used as receptors by neurotropic herpesviruses. My overall goal is to understand how herpes simplex virus (HSV) uses receptors from the nectin family for entry, spread and pathogenesis. Toward that goal, three lines of research are being developed:
- To determine how HSV uses and subverts the normal functions of nectin-1 during viral entry and spread.
- To define how the cell responds when nectin-1 engages cellular versus viral ligands.
- To define how binding of nectin-1 to HSV gD triggers virus entry.
Members of the nectin family interact with each other at various specialized cell contacts such as synapses in neurons or adherens junctions of the epithelium. Intracellular effects of ligand binding to nectins remain mostly unknown. Nectin-1, and nectin-2 are used by HSV and other alpha-herpesviruses to enter epithelial cells and neurons. The viral ligand for nectin-1 is the envelope glycoprotein D (gD) and this interaction is a crucial step for HSV entry. At the molecular level, this interaction induces conformational changes in gD that activate the complex mechanism leading to membrane fusion and entry. At the cellular level, gD interferes with the ability of nectin-1 to mediate cell aggregation. This may be the result of direct competition with nectin-1 natural ligands or by inducing an adverse cellular response. My interest is to understand how nectin-1 mediates cell adhesion and how HSV subverts this natural function during its entry into cells. I study interactions between nectin-1 and gD at the molecular and structural levels using proteins purified from the baculovirus expression system and cell models.
Studies of the mechanism of action and regulation of nectins at the cellular level are another facet of my research. First, I am looking at the cellular responses to nectin-1 binding at cell contacts during establishment of adherens junctions. Second I am looking at the signals mediated by nectin-1 during HSV infection. Recent developments in confocal live cell imaging make it possible to look directly at nectins in situ.
Various cell lines expressing nectin-1 tagged with GFP, YFP and CFP have been generated to assess the response of nectins upon ligand binding in real time.

Rotation projects:
1) Analysis of the effects of HSV infection on cell junctions. This project involves confocal microscopy, transfections, protein detection and HSV infection.
2) Analysis of virus entry and receptor dimerization using bimolecular fluorescence complementation. This project involves live cells confocal microscopy and HSV production/infection.

Selected Publications

Boesze-Battaglia, K, Brown, A, Walker, L, Besack, D, Zekavat, A, Wrenn, S, Krummenacher, C, Shenker, BJ: Cytolethal Distending Toxin-induced Cell Cycle Arrest of Lymphocytes Is Dependent upon Recognition and Binding to Cholesterol. Journal Of Biological Chemistry 284(16): 10650-10658, APR 17 2009.

Reske, A, Pollara, G, Krummenacher, C, Katz, DR, Chain, BM: Glycoprotein-dependent and TLR2-independent innate immune recognition of herpes simplex virus-1 by dendritic cells. Journal Of Immunology 180(11): 7525-7536, JUN 1 2008.

Heldwein, EE, Krummenacher, C: Entry of herpesviruses into mammalian cells. Cellular And Molecular Life Sciences 65(11): 1653-1668, JUN 2008.

De Regge, N, Nauwynck, HJ, Geenen, K, Krummenacher, C, Cohen, GH, Eisenberg, RJ, Mettenleiter, TC, Favoreel, HW: alpha-herpesvirus glycoprotein D interaction with sensory neurons triggers formation of varicosities that serve as virus exit sites. Journal Of Cell Biology 174(2): 267-275, JUL 17 2006.

Horvath, S, Prandovszky, E, Kis, Z, Krummenacher, C, Eisenberg, RJ, Cohen, GH, Janka, Z, Toldi, J: Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development. Journal Of Neurovirology 12(3): 161-170, JUN 2006.

Krummenacher, C, Supekar, VM, Whitbeck, JC, Lazear, E, Connolly, SA, Eisenberg, RJ, Cohen, GH, Wiley, DC, Carfi, A: Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO Journal 24(23): 4144-4153, DEC 7 2005.

Simpson, SA, Manchak, MD, Hager, EJ, Krummenacher, C, Whitbeck, JC, Levin, MJ, Freed, CR, Wilcox, CL, Cohen, GH, Eisenberg, RJ, Pizer, LI: Nectin-1/HveC mediates herpes simplex virus type 1 entry into primary human sensory neurons and fibroblasts. Journal Of Neurovirology 11(2): 208-218, APR 2005.

Krummenacher, C, Baribaud, F, de Leon, MP, Baribaud, I, Whitbeck, JC, Xu, RL, Cohen, GH, Eisenberg, RJ: Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology 322(2): 286-299, MAY 1 2004.

Linehan, MM, Richman, S, Krummenacher, C, Eisenberg, RJ, Cohen, GH, Iwasaki, A: In vivo role of nectin-1 in entry of herpes simplex virus type 1 (HSV-1) and HSV-2 through the vaginal mucosa. Journal Of Virology 78(5): 2530-2536, MAR 2004.

Krummenacher, C, Baribaud, I, Eisenberg, RJ, Cohen, GH: Cellular localization of nectin-1 and glycoprotein D during herpes simplex virus infection. Journal Of Virology 77(16): 8985-8999, AUG 2003.

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Last updated: 04/09/2014
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