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.
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Rebecca A
RA
Bozym
Stefanie A
SA
Morosky
Kwang S
KS
Kim
Sara
S
Cherry
Carolyn B
CB
Coyne
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