Biographical Sketch

Dr. Spear earned a BA degree in bacteriology and chemistry at Florida State University in 1964 and a PhD degree in virology at the University of Chicago in 1969. Her predoctoral research was on proteins of herpes simplex virus, under the guidance of Dr. Bernard Roizman, and her postdoctoral research was on development of the immune system in mice, with Dr. Gerald Edelman at The Rockefeller University. Dr. Spear held a faculty appointment at the University of Chicago from 1973 until 1987, at which time she joined the faculty of Northwestern University Medical School as the Guy and Anne Youmans Professor and Chair of Microbiology-Immunology.

Research Description

Mechanisms of herpes simplex virus entry into cells and virus-induced cell fusion; identification and characterization of cell surface carbohydrates and proteins required for viral entry and cell fusion; role of viral envelope proteins in viral entry and cell fusion; cell tropism and pathogenesis as determined by differential expression of multiple viral receptors in different cell types and variable ability of viral strains to use different receptors for entry.

Research Abstract

Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) cause lesions on the body surface, usually on mucosal membranes, and can enter sensory neurons to establish latent infections in peripheral ganglia. Reactivation of virus can result in recurrences of lesions at the site of initial infection. Rarely, the virus can invade the central nervous system and cause encephalitis. Newborn infants are especially susceptible to life-threatening disseminated disease affecting many organ systems. Whereas many cell types are targeted by the virus in newborn infants, infections in children and adults are more likely to be limited to epithelial cells, lymphoid cells, and cells of the nervous system.

Our research is directed toward defining the cell and viral factors required for HSV-1 and HSV-2 binding to, and penetration of, human cells and for viral spread by cell-cell fusion. Several years ago, we demonstrated that HSV-1 and HSV-2 bind to cells through interactions of the viral envelope glycoproteins gC and gB with cell surface glycosaminoglycans, preferentially heparan sulfate. Additional virus-cell interactions are required for viral penetration of the cell, which occurs by fusion of the virion envelope with a cell membrane. Recently, we have cloned several human cDNAs encoding cell surface proteins that can participate in this penetration by fusion. Each of these proteins is independently capable of mediating viral entry and virus-induced cell fusion. These proteins are differentially expressed on different human cell types and belong to different classes of cell surface proteins. One is a member of the TNF receptor family and three are related members of the immunoglobulin superfamily. It appears that all the human entry proteins identified to date are receptors for the virion glycoprotein gD. Differences exist in gD structure between HSV-1 and HSV-2 strains and even within each serotype. Although most viral strains tested can use any of the gD receptors for entry, preferences are evident, and one of the receptors is specific for HSV-2 strains.

Because HSV infections of mice provide a good model for human disease, we are identifying mouse as well as human receptors for HSV entry and exploring expression patterns of these receptors and genetic differences in cell receptors and viral glycoproteins that influence disease and pathogenicity.

Publications

Shieh M.T., WuDunn D., Montgomery R.I., Esko J.D., and Spear P.G. 1992. Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J. Cell. Biol., 116:1273-1281.

Dean H.J., Terhune S.S., Shieh M.T., Susmarski N., and Spear P.G. 1994. Single amino acid substitutions in gD of herpes simplex virus 1 confer resistance to gD-mediated interference and cause cell type-dependent alterations in infectivity. Virology, 199:67-80.

Montgomery R.I., Warner M., Lum B. and Spear P.G. 1996. Herpes simplex virus 1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell, 87:427-436.

Whitbeck J.C., Peng C., Lou H., Xu R., Willis S.H., Ponce de Leon M., Peng T., Nicola A.V., Montgomery R.I., Warner M.S., Soulika A.M., Spruce L.A., Moore W.T., Lambris J.D., Spear P.G., Cohen G.H., and Eisenberg, R.J. 1997. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J. Virol. 71:6083-6093.