Abstract
West Nile virus (WNV) is an enveloped positive-stranded RNA virus that causes meningitis, encephalitis, and acute flaccid paralysis in humans. There are no therapeutic agents available for use against WNV infection. Alpha-2 macroglobulin (A2M) is a major plasma proteinase inhibitor that also has important role in immune modulation. In mice, pregnancy zone protein (PZP) and murinoglobulin-1 (MUG-1) are two close homologous of human A2M. In this study, we investigated the role of PZP and MUG-1 proteins in the pathogenesis of WNV infection in mice. Adult C57BL/6J wild-type and PZP/MUG-1 double knockout (DKO) mice were inoculated subcutaneously with WNV and mortality, virus burden, and immune responses were analyzed. Infection of wild-type (WT) mice with WNV resulted in significantly high morbidity and mortality. In comparison, no mortality was observed in DKO mice, suggesting that PZP and MUG-1 play a deleterious role in WNV infection. Increased survival in WNV-infected DKO mice was associated with significantly low viral burden in serum, spleen, kidney, and brain compared to WT mice. In addition, significantly reduced levels of type 1 interferon and WNV-specific antibodies were observed in the DKO mice compared to WT mice. We further demonstrated that protein levels of inflammatory cytokines and chemokines in the serum, spleen, and brain were significantly reduced in DKO mice compared to WT mice. Collectively our data demonstrate that lack of PZP and MUG-1 restricts the pathogenesis of WNV infection in mice.
Highlights
West Nile virus (WNV) is a single-stranded positive-sense RNA virus that targets neurons to cause potentially lethal encephalitis
NY99 was highly lethal and resulted in 90% mortality. no mortality was observed in double knockout (DKO) mice infected with WT mice inoculated with 100 plaqueforming units (PFU) of WNV 1,000 or 100 PFU of WNV, indicating a detrimental role for pregnancy zone protein (PZP) and MUG-1 proteins during WNV infection (Figure 1A)
We demonstrate that lack of PZP and MUG-1 proteins restricts the pathogenesis of WNV infection in mice
Summary
West Nile virus (WNV) is a single-stranded positive-sense RNA virus that targets neurons to cause potentially lethal encephalitis. WNV is related to other important flavivirus pathogens such as dengue virus, Japanese encephalitis virus (JEV) and yellow fever virus. WNV is an enveloped virus with genome length of 11 kb encoding a large single polypeptide. PZP, MUG-1 in WNV Infection which is cleaved into envelope glycoprotein E, transmembrane protein M, capsid protein, and several non-structural proteins. Since its initial introduction into New York in 1999, outbreaks of WNV-associated encephalitis (WNVE) have occurred in all 48 contiguous states, resulting in hundreds of deaths (Brinton, 2002). WNV continues to spread and cause human disease in new areas of the world. There is no specific treatment or vaccine exist for treating individuals with WNV infection, and the WNV disease pathogenesis is not completely understood
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