Abstract
Japanese encephalitis virus (JEV) is a single stranded RNA virus that infects the central nervous system leading to acute encephalitis in children. Alterations in brain endothelial cells have been shown to precede the entry of this flavivirus into the brain, but infection of endothelial cells by JEV and their consequences are still unclear. Productive JEV infection was established in human endothelial cells leading to IFN-β and TNF-α production. The MHC genes for HLA-A, -B, -C and HLA-E antigens were upregulated in human brain microvascular endothelial cells, the endothelial-like cell line, ECV 304 and human foreskin fibroblasts upon JEV infection. We also report the release/shedding of soluble HLA-E (sHLA-E) from JEV infected human endothelial cells for the first time. This shedding of sHLA-E was blocked by an inhibitor of matrix metalloproteinases (MMP). In addition, MMP-9, a known mediator of HLA solubilisation was upregulated by JEV. In contrast, human fibroblasts showed only upregulation of cell-surface HLA-E. Addition of UV inactivated JEV-infected cell culture supernatants stimulated shedding of sHLA-E from uninfected ECV cells indicating a role for soluble factors/cytokines in the shedding process. Antibody mediated neutralization of TNF-α as well as IFNAR receptor together not only resulted in inhibition of sHLA-E shedding from uninfected cells, it also inhibited HLA-E and MMP-9 gene expression in JEV-infected cells. Shedding of sHLA-E was also observed with purified TNF-α and IFN-β as well as the dsRNA analog, poly (I:C). Both IFN-β and TNF-α further potentiated the shedding when added together. The role of soluble MHC antigens in JEV infection is hitherto unknown and therefore needs further investigation.
Highlights
Viral encephalitis caused by Japanese encephalitis virus (JEV) is a mosquito-borne disease that is prevalent in different parts of India and South East Asia [1,2]
Induction of HLA Class I by JEV Infection human brain microvascular endothelial cells (HBMEC), ECV and Human foreskin fibroblasts (HFF) cells were first tested for their ability to support JEV infection
In this study we demonstrate that, JEV infection in HBMEC and ECV cells resulted in production of IFN-b, TNF-a and MMP9 with upregulation of MHC-I genes
Summary
Viral encephalitis caused by Japanese encephalitis virus (JEV) is a mosquito-borne disease that is prevalent in different parts of India and South East Asia [1,2]. JEV is a positive sense single stranded RNA virus that belongs to the Flavivirus genus of the family Flaviviridae [3] This neurotropic virus as well as its ability to cause encephalitis has been well studied with respect to its structural, pathological, immunological and epidemiological aspects [4,5,6,7,8]. Limited amplification of JEV was shown in rat endothelial cells [10] Flaviviruses such as West Nile (WNV) and dengue viruses [11,12,13] have been shown to infect endothelial cells and several neurotropic viruses that infect brain parenchymal cells infect endothelial cells [14]. These observations lend support to the speculations that virion budding on the parenchymal side of infected endothelial cells [15], transcytosis across cerebral capillary endothelial cells and infiltration of infected leukocytes across a compromised blood brain barrier (BBB) could be the mechanisms of CNS invasion [16,17]
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