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Published online 20 October 2003. doi:10.1083/jcb.200301084
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© The Rockefeller University Press, 0021-9525/2003/10/283 $8.00
The Journal of Cell Biology, Volume 163, Number 2, 283-293


Article

Herpes simplex virus triggers activation of calcium-signaling pathways

Natalia Cheshenko, Brian Del Rosario, Craig Woda, Daniel Marcellino, Lisa M. Satlin and Betsy C. Herold

Department of Pediatrics and Microbiology, Mount Sinai School of Medicine, New York, NY 10029

Address correspondence to Betsy C. Herold, Dept. of Pediatrics and Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1657, New York, NY 10029. Tel.: (212) 241-5272. Fax: (212) 426-4813. email:betsy.herold{at}mssm.edu

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy.

Key Words: focal adhesion kinase; viral entry; membrane fusion; IP3; tyrosine phosphorylation


Abbreviations used in this paper: 2-APB, 2-aminoethoxydiphenylborate; [Ca2+]i, intracellular calcium concentration; {Delta}, mean change; gC, gB, gD, gH, gL, glycoprotein C, B, D, H, or L, respectively; HCMV, human cytomegalovirus; HI, heat-inactivated; HSV, herpes simplex virus; IP3, 1,4,5-triphosphate; moi, multiplicity of infection; odu, optical densitometry units; pfu, plaque-forming units; Tg, thapsigargin; VSV, vesicular stomatitis virus.


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