No abstract

Endothelial cells play an important role in transmission of JEV across the blood brain barrier while fibroblasts are involved in peripheral spread of infection. JEV, a neurotropic flavivirus was found to replicate and establish productive infection in human endothelial cell lines leading to production of IFN-β and TNF-α. Expression of HLA-E mRNA and protein showed significant upregulation during JEV infection of the human endothelial cell line, ECV304, human brain microvascular endothelial cells (HBMECs) and a primary human foreskin fibroblast (HFF) cell line. This is the first report to show that the infection of endothelial cells by JEV can result in the release of HLA-E as soluble molecules which is mediated by matrix metalloproteinases. However, HFF cells showed only upregulation of HLA-E on cell surface upon JEV infection. Experiments using inhibitors of MAPK and NF-κB suggest that the release of soluble HLA-E upon JEV infection was dependent on the MAPK pathway but independent of NF-kB. The soluble HLA-E that was released upon JEV infection was functionally active since it inhibited the IL-2 and PMA induced phosphorylation of ERK1/2 in NK cell lines. Inhibition of ERK1/2 phosphorylation has been shown to inhibit cytotoxicity of NK cells by inhibiting mobilization of granzyme granules to immunological synapse. Thus, it is possible that release of soluble HLA-E can have far reaching consequences on activation of NK cells as well as CTLs upon JEV infection.