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Education/Professional Honors and Credentials
- Postdoctoral Fellow, Princeton University, Princeton, N.J.
1966-1968
- Ph.D. in Microbiology, University of Pennsylvania, 1965
- A.B. in Biology, Bryn Mawr College, 1960
- Fellow, American Academy of Microbiologists
- Fellow, American Association for the Advancement of Science
Research Interests
Dr. Eisenberg's overall goal is to understand the mechanisms by which enveloped DNA viruses enter susceptible cells. Her research is a collaborative effort with long-term colleague, Dr. Gary H. Cohen, Professor and Chair of the Department of Microbiology at Penn Dental Medicine; while Dr. Eisenberg is a member of the School of Veterinary Medicine faculty with a secondary appointment at Penn Dental Medicine, her lab is at the Dental School with Dr. Cohen. Their research is primarily focused on the herpes simplex virus (HSV) and has more recently included work on poxvirus entry.
HSV entry requires the binding of glycoprotein D (gD) to either HVEM or nectin-1. This interaction triggers virus-cell fusion involving three other HSV glycoproteinsHVEM is a member of the TNF receptor superfamily. Nectin-1 is an adhesion molecule located at the gD adherens junctions of cells and is a member of the Ig superfamily. A major accomplishment was to solve the three-dimensional structure of gD bound to HVEM. The structure of this complex has enabled them to carry out structure-based mutagenesis of both proteins. Three additional gD structures have shown that the binding sites for both receptors are hidden in the native protein. Receptor binding necessitates a major conformational change in gD that is also required to properly trigger fusion. In collaboration with Drs. Katya Heldwein and Steve Harrison of Harvard Medical School, they solved the 3-dimensional structure of gB, a highly conserved protein that is a critical component of the fusion machinery. Studies to understand the structure and function of gH/gL, the other component of the fusion complex, is also an active area of the team's research.
Drs. Eisenberg and Cohen are exploring how the gD/receptor interaction triggers the next steps of virus entry and cell fusion. They are also using bimolecular complementation to follow protein-protein interactions that play important roles in the entry process and have found that gD triggers an interaction between gB and gH/gL simultaneously with the triggering of cell-cell fusion. Recent studies suggest that this interaction is a critical step, leading to fusion. In addition, one of the HSV receptors, HVEM, binds to a T-cell regulatory molecule called BTLA. This protein competes with HSV gD and the two researchers are investigating the significance of this competition for HSV pathogenesis.
Following the events of September 11, Drs. Eisenberg and Cohen began work on vaccinia virus (VACV) glycoproteins. A major goal of theirs is to develop a subunit vaccine against smallpox using proteins from VACV or from variola virus (smallpox) as a safer vaccine than the present one. Such a vaccine could be used for immunocompromised patients who cannot tolerate the current live virus vaccines and could also be used in a prime-boost strategy. A second goal is to understand the mechanism of VACV entry into cells, using techniques and approaches they have applied to studies of HSV entry. Importantly, they have shown that a combination of three envelope proteins of VACV protects mice against a lethal VV challenge. To understand the role of each of these proteins (and others) in poxvirus entry, the researchers are taking similar approaches to those used in their herpes virus work. VACV, like HSV, can use more than one pathway for entry and they also have evidence that at least one of the proteins being studied may be involved in receptor binding.
Selected Publications
- Krummenacher C, Supekar VM, Whitbeck JC, Lazear E, Connolly SA, Eisenberg RJ, Cohen GH, Wiley DC and Carfi A. 2005. Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO J. 24:4144-4153.
- Whitbeck JC, Zuo Y, Milne RS, Cohen GH, and Eisenberg RJ. 2006. Stable association of herpes simplex virus with target membranes is triggered by low pH in the presence of the gD receptor, HVEM. J Virol. 80:3773-3780.
- Heldwein E, Lou H, Bender F, Cohen GH, Eisenberg RJ, and Harrison SC. 2006. Crystal structure of glycoprotein B from Herpes Simplex Virus 1. Science. 313:217-220.
- Cairns TM, Shaner MS, Zuo Y, Ponce-de-Leon M, Baribaud I, Eisenberg RJ, Cohen GH, and Whitbeck JC. 2006. Epitope Mapping of Herpes Simplex Virus Type 2 gH/gL Defines Distinct Antigenic Sites, Including Some Associated with Biological Function. J. Virol. 80:2596-2608.
- Hannah BP, Heldwein EE, Bender FC, Cohen GH and Eisenberg RJ. 2007. Mutational evidence of internal fusion loops in HSV glycoprotein B. J. Virol. 81:4858-4865.
- Aldaz-Carroll L, Xiao Y, Whitbeck JC, Ponce de Leon M, Lou H, Kim M, Yu J, Reinherz EL, Isaacs SN, Eisenberg RJ and Cohen GH. 2007. Major neutralizing sites on vaccinia virus glycoprotein B5 are expressed differently on variola ortholog B6. J. Virol. 81: 8131-8139.
- Bender, FC, Samanta M, Heldwein EE, Ponce de Leon, M, Bilman E, Lou H, Eisenberg RJ and Cohen GH. 2007. Antigenic and mutational analyses of herpes simplex virus glycoprotein B reveal four functional regions. J. Virol 81:3827-3841.
- Atanasiu D, Whitbeck JC, Cairns TM, Reilly B, Cohen GH and Eisenberg RJ. 2007. Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion. Proc. Nat'l Acad Sci USA. 104:18718-18723.
- Lazear, E, Carfi A, Whitbeck JC, Cairns TM, Krummenacher C, Cohen GH and Eisenberg RJ. 2007. Engineered disulfide bonds in herpes simplex virus type 1 gD separate receptor binding from fusion initiation and viral entry. J. Virol. 82(2):700-709.
- Xiao, Y, Aldaz-Carroll L, Ortiz AM, Whitbeck JC, Alexander, E, Lou H, Davis, HL, Braciale TJ, Eisenberg RJ, Cohen GH, and Isaacs SN. 2007. A protein-based smallpox vaccine protects mice from vaccinia and ectromelia challenge when given as a prime and single boost. Vaccine. 25:1214-24.
- Stiles, KM, Milne, RSB, Cohen GH, Eisenberg, RJ and Krummenacher C. 2008. The herpes simplex virus receptor nectin-1 is down-regulated after trans-interaction with glycoprotein D. Virology. 373:98-111.
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