Carl Ware
e-mail: carl_ware@liai.org |
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The immune system has evolved specific mechanisms to recognize and eliminate virus-infected cells, yet many viruses, once acquired persist in the host, despite the presence of a competent immune system. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines and receptors. These cytokines are critical regulators of the immune system and several are essential for defense against viral pathogens. Several different viruses have evolved specific mechanisms that target members of the TNF superfamily, and thus may serve to promote virus persistence or pathogenicity.
TNF, LYMPHOTOXINS AND LIGHT
TNF-related ligands are type II transmembrane
proteins that assemble into trimers on the surface of activated lymphocytes.
These ligands initiate cell death, or growth and differentiation through
specific cell surface receptors that form a corresponding superfamily
defined by a signature cysteine-rich ectodomain. The signaling pathways
activated by TNF receptors utilize distinct families of second messengers
that include the TRAFs and death domain (DD) family. Our laboratory
has been involved in the discovery of several members of this superfamily,
including the Lymphotoxin (LT)-ab complex1 and LIGHT2,
and their receptors. Along with TNF, these proteins represent the "immediate"
family that forms an integrated communication network essential for
host defense and lymphoid organogenesis. Gene deletion studies have
shown that LTab, and the TNF and LTb receptors, are responsible for
the development of secondary lymph organs, and for the formation of
germinal centers following antigen stimulation. The molecular signaling
pathways underlying these physiologic processes are under study using
biochemical and molecular genetic approaches in mouse and tissue culture
models. LIGHT interacts with herpesvirus entry mediator (HVEM) and the
LTbR, however its role is just now being elucidated.
VIRAL EVASION STRATEGIES: VIROKINES AND VIROCEPTORS
An emerging theme is the extensive degree that
viruses have taken to alter the activity of the TNF superfamily. Several
examples of specific viral gene products, from both DNA and RNA viruses,
are known to directly modulate or mimic members of the TNF superfamily.
For example, the envelope glycoprotein gD of herpes simplex virus is
a virokine that specifically mimics LIGHT binding to HVEM2.
Other examples include LMP1 protein of Epstein-Barr virus3,
Hepatitis C core protein4 and the adenovirus E3 proteins5.
Together, these examples are revealing the complex molecular interface
between the immune system and viral pathogens.
1Browning, J. L., Ngam-ek, A., Lawton, P., DeMarinis, J., Tizard, R., Chow, E.P., Hession, C., Greco, B., Foley, S. and Ware, C.F. 1993. Lymphotoxin-_: A new member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72:847-856.
2Mauri, D.N., Ebner, R., Montgomery, R.I., Kochel, K.D., Cheung, T.C., Yu, G.-L., Ruben, S., Murphy, M., Eisenberg, R.J., Cohen, G.H., Spear, P.G. and Ware, C.F. 1998. LIGHT, a new member of the TNF superfamily, and lymphotoxin (LT)a are ligands for herpesvirus entry mediator (HVEM). Immunity 8: 20-31.
3Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C.F. and Kieff, E. 1995. The Epstein-Barr Virus transforming protein LMP-1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80:389-399.
4Matsumoto, M., Hsieh, T-y, Zhu, N., VanArsdale, T., Hwang, S.B., Jeng, K-S, Gorbalenya, A.E., Lo, S-Y, Ou, J-h, Ware, C.F. and Lai, M. M-C. 1997. Hepatitis C virus core protein interacts with the cytoplasmic tail of Lymphotoxin-b_receptor. J. Virology 71:1301-1309.
5Shisler, J., Walter,
B.N., Ware, C.F. and Gooding, L.R. 1997. The adenovirus E3-10.4K/14.5
complex mediates loss of cell surface Fas (CD95) and resistance to Fas-induced
apoptosis. J. Virology 71:8299-8306.
Carl F. Ware received his Ph.D. from UC Irvine. He is head of the Division of Molecular Immunology at the La Jolla Institute for Allergy and Immunology.
