Abstract
West Nile virus (WNV) is a flavivirus that has disseminated globally as a significant cause of viral encephalitis in humans. MircoRNA-155 (miR-155) regulates various aspects of innate and adaptive immune responses. We previously reported that WNV infection induces upregulation of miR-155 in mice brains. In the current study, we demonstrate the critical role of miR-155 in restricting the pathogenesis of WNV infection in mice. Compared to wild-type (WT) mice, miR-155 knockout mice exhibited significantly higher morbidity and mortality after infection with either a lethal strain, WNV NY99, or a non-lethal strain, WNV Eg101. Increased mortality in miR-155−/− mice was associated with significantly high WNV burden in the serum and brains. Protein levels of interferon (IFN)-α in the serum and brains were higher in miR-155−/− mice. However, miR-155−/− mice exhibited significantly lower protein levels of anti-viral interleukin (IL)-1β, IL-12, IL-6, IL-15, and GM-CSF despite the high viral load. Primary mouse cells lacking miR-155 were more susceptible to infection with WNV compared to cells derived from WT mice. Besides, overexpression of miR-155 in human neuronal cells modulated anti-viral cytokine response and resulted in significantly lower WNV replication. These data collectively indicate that miR-155 restricts WNV production in mouse and human cells and protects against lethal WNV infection in mice.
Highlights
West Nile virus (WNV) is a flavivirus that causes severe encephalitis in humans and horses.WNV is maintained in an enzootic cycle between mosquitoes and birds [1,2]
We previously reported that WNV infection induces significant upregulation of miR-155 in mice brains [26]
We demonstrate the critical role of miR-155 in restricting the pathogenesis of WNV infection in mice
Summary
West Nile virus (WNV) is a flavivirus that causes severe encephalitis in humans and horses.WNV is maintained in an enzootic cycle between mosquitoes and birds [1,2]. West Nile virus (WNV) is a flavivirus that causes severe encephalitis in humans and horses. Persistence of WNV infection can cause long-lasting sequelae such as a chronic renal disease [3,4]. MicroRNAs (miRNAs) are a group of small RNAs involved in the regulation of several pathways including cell cycle, apoptosis, and immune response [5,6]. Multiple studies have reported that miRNAs possess a fundamental role in host-viral interactions as the miRNAs of infected cells can influence the ability of the virus to replicate or spread [7,8,9]. It is known that endogenous miRNAs inhibit replication of a number of RNA viruses including HIV-1, Ebola virus and vesicular stomatitis virus [10,11,12,13]. Over-expression of miRNA-30e, let-7c, and miRNA-126-5p inhibits dengue virus (DENV)
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