Herpes simplex virus triggers activation of calcium-signaling pathways.
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.
Deparment of Pediatrics and Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Natalia
N
Cheshenko
Brian
B
Del Rosario
Craig
C
Woda
Daniel
D
Marcellino
Lisa M
LM
Satlin
Betsy C
BC
Herold
D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018259:Herpesvirus 1, Human / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014709:Vero Cells
D001896:Boron Compounds; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; C048925:herpes simplex virus, type 1 protein ICP4; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019284:Thapsigargin; D014700:Verapamil; C109986:2-aminoethoxydiphenyl borate; D009543:Nifedipine; D002118:Calcium