Expression of non-classical HLA molecule, HLA-E during Japanese encephalitis virus (JEV) infection

¹Dept of Biochemistry, Indian Institute of Science (IISc), Bangalore, India ²Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro, Italy ³Division of Pediatric Infectious Diseases, Johns Hopkins Univ School of Medicine, Baltimore, MD

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-B 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.