Research:
Dr. Keith Jerome holds a B.S. in Chemistry from Georgetown College, and M.D. and Ph.D. degrees from Duke University, where his thesis focused on T cell antigens expressed by breast tumors. He did residency and fellowship training at the University of Washington. His research focuses on failures of T cell immunity, especially during chronic viral infections.
Viral modulation of apoptosis pathways. Dr. Jerome has a long-standing interest in the virus-host interaction, including the effect of viral infections on the regulation of cellular apoptosis. His laboratory demonstrated that cells infected with HSV become refractory to apoptosis. Modulation of apoptosis has subsequently become a major field of interest for herpes virologists. Dr. Jerome demonstrated that the anti-apoptotic effect of HSV was due to the expression of two genes, Us5 and Us3. HSV-infected cells are protected from apoptosis induced by cytotoxic T lymphocytes (CTL), suggesting that this may constitute a form of immune evasion. The Us5 gene product in particular protects infected or transfected cells from apoptosis induced by either of the major CTL-mediated pathways of cell killing (granzyme B or fas ligand). The potential in vivo significance of apoptosis inhibition is underscored by the finding that all clinical isolates of HSV tested to date exhibit anti-apoptotic activity. Most recently, Dr. Jerome has demonstrated that the Us5 gene product blocks apoptosis in a manner unique among viral proteins, via direct binding to subunit 6 of F0F1 ATP synthase.
Viral inactivation of CTL activity. Dr. Jerome also has an interest in a second aspect of the virus-host interaction, in which he has demonstrated that HSV-infected cells transduce a negative signal to cytotoxic T lymphocytes. These "inactivated" CTL are not infected by HSV, and yet are profoundly deficient in their ability to respond to stimulation via their T cell receptors. Inactivation of CTL is dependent upon the expression of the HSV kinase Us3 in the infected cell. Current work focuses on elucidation of the mechanism transmitting the inactivating signal, and on defining the pathways for receipt of the inactivating signal. These studies have prompted the development of novel methods for detecting CTL-induced cytotoxicity. The results may have profound implications for our understanding of T cell regulation, and may provide targets for pharmacologic manipulation.
Selected Publications:
KR Jerome, R Fox, Z Chen, AE Sears, H-Y Lee, and L Corey. Herpes simplex virus inhibits apoptosis through the action of two genes, US5 and US3. Journal of Virology. 73:8950-8957. 1999.
KR Jerome, Z Chen, R Lang, MR Torres, J Hofmeister, S Smith, R Fox, CJ Froelich, and L Corey. Herpes simplex virus and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or fas. Journal of Immunology. 167:3928-3935. 2001.
KR Jerome, DD Sloan, and MA Aubert. Measuring T cell-mediated cytotoxicity using antibody to activated caspase 3. Nature Medicine. 9:4-5. 2003.
DD Sloan, G Zahariadis, CM Posavad, N Pate, S Kussick, and KR Jerome. Cytotoxic T lymphocytes are inactivated by HSV-infected cells expressing a viral protein kinase. Journal of Immunology. 171: 6733-6741. 2003.
KR Jerome and L Corey. The danger within. New England Journal of Medicine. 350: 411-412. 2004.
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