Krause Keeton, Azouz Francine, Nakano Eileen, Nerurkar Vivek R, Kumar Mukesh
Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.
Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA, United States.
Front Microbiol. 2019 Feb 13;10:259. doi: 10.3389/fmicb.2019.00259. eCollection 2019.
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.
西尼罗河病毒（WNV）是一种包膜正链RNA病毒，可导致人类患脑膜炎、脑炎和急性弛缓性麻痹。目前尚无针对WNV感染的治疗药物。α-2巨球蛋白（A2M）是一种主要的血浆蛋白酶抑制剂，在免疫调节中也发挥着重要作用。在小鼠中，妊娠区蛋白（PZP）和鼠球蛋白-1（MUG-1）是人类A2M的两个紧密同源物。在本研究中，我们调查了PZP和MUG-1蛋白在小鼠WNV感染发病机制中的作用。将成年C57BL/6J野生型和PZP/MUG-1双敲除（DKO）小鼠皮下接种WNV，并分析死亡率、病毒载量和免疫反应。WNV感染野生型（WT）小鼠导致显著高的发病率和死亡率。相比之下，DKO小鼠未观察到死亡，这表明PZP和MUG-1在WNV感染中起有害作用。与WT小鼠相比，WNV感染的DKO小鼠存活率增加与血清、脾脏、肾脏和大脑中显著低的病毒载量相关。此外，与WT小鼠相比，DKO小鼠中1型干扰素和WNV特异性抗体水平显著降低。我们进一步证明，与WT小鼠相比，DKO小鼠血清、脾脏和大脑中炎症细胞因子和趋化因子的蛋白水平显著降低。我们的数据共同表明，缺乏PZP和MUG-1可限制小鼠WNV感染的发病机制。
