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.