Release of intracellular calcium stores facilitates coxsackievirus entry into polarized endothelial cells.
Group B coxsackieviruses (CVB) are associated with viral-induced heart disease and are among the leading causes of aseptic meningitis worldwide. Here we show that CVB entry into polarized brain microvasculature and aortic endothelial cells triggers a depletion of intracellular calcium stores initiated through viral attachment to the apical attachment factor decay-accelerating factor. Calcium release was dependent upon a signaling cascade that required the activity of the Src family of tyrosine kinases, phospholipase C, and the inositol 1,4,5-trisphosphate receptor isoform 3. CVB-mediated calcium release was required for the activation of calpain-2, a calcium-dependent cysteine protease, which controlled the vesicular trafficking of internalized CVB particles. These data point to a specific role for calcium signaling in CVB entry into polarized endothelial monolayers and highlight the unique signaling mechanisms used by these viruses to cross endothelial barriers.
Bozym
Rebecca A
RA
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Morosky
Stefanie A
SA
Kim
Kwang S
KS
Cherry
Sara
S
Coyne
Carolyn B
CB
D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002154:Calpain / Q000378:metabolism / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology / Q000821:virology; D004770:Enterovirus / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism / Q000502:physiology / Q000821:virology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism / Q000502:physiology; D042541:Intracellular Space / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism / Q000502:physiology; D053586:Virus Internalization
D053496:Inositol 1,4,5-Trisphosphate Receptors; D051966:Phospholipase C gamma; D002154:Calpain; D002118:Calcium