Claude Krummenacher, Ph.D.

Office

University of Pennsylvania

School of Dental Medicine

240 S. 40^th Street, Philadelphia PA 19104

Levy Building, Rm 215

Phone: 215 898 6553

FAX: 215 898 8385

krumm@biochem.dental.upenn.edu

Position

Assistant Professor
Department of Biochemistry
UPENN School of Dental Medicine
(From July 1, 2007)

Research Assistant Professor
Department of Microbiology
UPENN School of Dental Medicine
(Until June 30, 2007)

Education

Ph.D. 1995

University of Lausanne, Switzerland

Links

Lab webpage at the UPENN School of Medicine, Department of Microbiology http://www.med.upenn.edu/micro/faculty/krumm.html

Research Interests

I am interested in the functions of nectins, a family of cell adhesion molecules used as cellular receptors by neurotropic herpesviruses. This subfamily of immunoglobulin-like proteins contains at least five members which are involved in cell-cell adhesion and formation of intercellular junctions. Nectins interact with each other directly in a homo- or heterotypic fashion at various specialized cell contacts such as synapses or adherens junctions of the epithelium. Nectins are involved in various aspects of physiology and development. Nectin-1 plays a role in ocular and craniofacial development. In human, nectin-1 deficiency is associated with cleft lip/palate ectodermal dysplasia (CLPED1). Nectin-1, and -2 are used bya-herpesviruses to enter epithelial cells and neurons. Nectin-1 and an unrelated receptor from the TNF receptor family (HVEM) act as a major receptors for herpes simplex viruses (HSV) by interacting with the viral envelope glycoprotein D (gD).

The critical roles of nectins in cell adhesion and their activity as virus receptors make them a particularly interesting family of cell surface proteins. Complementary approaches (structural, biochemical and functional) are used to understand the roles and mechanism of action of cellular nectins in tissue organization and viral pathogenesis.

Studies of HSV entry into cells: my goal is to understand how the virus subverts the natural functions of nectins during virus entry into cells and spread in tissues. I am interested in studying the gD-receptor interactions as part of the complex molecular process that leads to membrane fusion between the cell and the virus. The mechanism by which receptor binding triggers a set of events leading to membrane fusion is investigated at the structural and functional levels. In addition, HSV can enter cells by fusion on the cell surface but opts for an endocytic pathway to enter many cell types. The molecular and structural determinants of gD and its receptor in the selection of entry pathways are of particular interest.

Studies of interactions between nectin-1 and its natural ligands. The availability of several ligands (nectin-1, nectin-3 and gD), makes this system particularly attractive to study cellular responses to nectin-1 stimulation in cell adhesion. The mode of action and regulation of nectins are studied at the functional level. In addition to standard biochemical and functional assays using purifies proteins, recent developments in live cells imaging make it possible to look directly at nectins in situ. We can follow formation and dissociation of cell contacts during establishement of junctions and during HSV infection.

Recent publications: PUBMED search

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=Krummenacher%20C

 Selected publications:

Geraghty R.J., C. Krummenacher, R.J. Eisenberg, G.H. Cohen and P.G. Spear. 1998. Entry of alphaherpesviruses mediated by poliovirus receptor related protein 1 and poliovirus receptor. Science. 280:1618-1620.

Krummenacher C., A.V. Nicola, J.C. Whitbeck, H. Lou, W. Hou, J.D. Lambris, R.J. Geraghty, P.G. Spear, G.H. Cohen and R.J. Eisenberg. 1998. Herpes Simplex Virus glycoprotein D can bind to poliovirus receptor related protein 1 (PRR1/HveC) or herpes virus entry mediator (HVEM/HveA), two structurally unrelated mediators of virus entry. J. Virol.72:7064-7074.

Krummenacher, C., A.H. Rux, J.C. Whitbeck, M. Ponce de Leon, H. Lou, I. Baribaud, W. Hou, C. Zou, R.J. Geraghty, P.G. Spear, R.J. Eisenberg and G.H. Cohen. 1999. The first Immunoglobulin-like domain of HveC is sufficient to bind herpes simplex virus gD with full affinity while the third domain is involved in oligomerization of HveC. J. Virol. 73:8127-8137.

Krummenacher, C., I. Baribaud, M. Ponce de Leon, J.C. Whitbeck, H. Lou, G.H. Cohen and R.J. Eisenberg. 2000. Localization of a binding site for herpes simplex virus glycoprotein D on the herpesvirus entry mediator C using anti-receptor monoclonal antibodies. J. Virol. 74: 10863-10872.

Miller, C.G., C. Krummenacher, R.J. Eisenberg, G.H. Cohen and N.W. Fraser. 2001. Development of a syngenic murine B16 cell line-derived melanoma susceptible to destruction by neuroattenuated HSV-1. Molecular Therapy. 3: 160-168.

Carfi, A., S.H. Willis, J.C. Whitbeck, C. Krummenacher, G.H. Cohen, R.J. Eisenberg and D.C. Wiley. 2001. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Molecular Cell. 8: 169-179.

Krummenacher, C., I. Baribaud, J.F. Sanzo, G.H. Cohen and R.J. Eisenberg. 2002. Effects of herpes simplex virus on structure and function of nectin-1/HveC. J. Virol. 76: 2424-2433.

Krummenacher, C., I. Baribaud, R.J. Eisenberg and G.H. Cohen. 2003. Cellular localization of nectin-1 and glycoprotein D during herpes simplex virus infection. J. Virol. 77: 8985-8999.

Linehan, M., S. Richman, C. Krummenacher, R.J. Eisenberg, G.H. Cohen and A. Iwasaki. 2004. In vivo role of nectin-1 in entry of HSV-1 and HSV-2 through the vaginal mucosa. J. Virol. 78(5): 2530-2536 and cover.

Krummenacher, C., F. Baribaud, M. Ponce de Leon, I. Baribaud, J.C. Whitbeck, R. Xu, G.H. Cohen and R.J. Eisenberg. 2004. Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology 332: 286-299.

Simpson S. A., M. D.Manchak, E.J. Hager, C. Krummenacher, J. C. Whitbeck, M. J. Levin, C. R. Freed, C. L. Wilcox, G. H. Cohen, R. J. Eisenberg and L. I. Pizer. 2005. Nectin-1/HveC mediates herpes simplex type-1 entry into primary human sensory neurons and fibroblasts. J. Neurovirol. 11:208-218.

Krummenacher, C., V.M. Supekar, J.C. Whitbeck, E. Lazear, S.C. Connolly, R.J. Eisenberg, G.H. Cohen, D.C. Wiley and A. Carfi. 2005. Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO J. 24:4144-4153.

Horwath S, E. Prandovszky, Z. Kis, C. Krummenacher, R.J. Eisenberg, G.H. Cohen, Z. Janka and J. Toldi. 2006. Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development. J. Neurovirol. 12:161-170.

De Regge, N., H.J. Nauwynck, K. Geenen, C. Krummenacher, G.H. Cohen, R.J. Eisenberg, T.C. Mettenleiter and H.W. Favoreel. 2006. Alpha-herpes virus gD interaction with sensory neurons triggers formation of varicosities that serves as virus exit sites. J. Cell Biol. 174:267-275. 

Krummenacher, C., A.Carfi, R.J. Eisenberg and G.H. Cohen. 2007. Herpesvirus entry into cells: The Enigma Variations. In S. Pöhlmann and G. Simmons, eds. Viral entry into host cells. Landes Bioscience. Vol. in press. Online edition: http://www.eurekah.com/chapter/3035