The role of interleukin 22 in West Nile virus pathogenesis in mice

描述（由申请人提供）：本提案是利用小鼠模型表征白细胞介素22 (IL-22)， il -10相关细胞因子家族的成员，在西尼罗脑炎发病机制中的作用。IL-22与慢性炎症性疾病和感染性疾病都有关系。一方面，IL-22参与银屑病和多发性硬化症的发病。另一方面，IL-22在肝炎期间保护肝脏免受免疫系统介导的损伤，帮助维持上皮屏障并诱导上皮分泌抗微生物肽，以应对细胞外病原体感染，如肺炎克雷伯菌。然而，据我们所知，IL-22在病毒感染中的体内作用在很大程度上仍然难以捉摸。西尼罗河病毒（WNV）是一种嗜神经的ssRNA黄病毒，自1999年以来在美国已造成1000多人死亡。然而，目前还没有人类疫苗或专门的治疗方法。有趣的是，我们最近发现IL-22不影响先天免疫反应和西尼罗河病毒在外周系统的传播，但促进了西尼罗河脑炎的发病机制。因此，我们建议测试IL-22拮抗剂的预防/治疗潜力，并假设IL-22促进西尼罗河病毒进入中枢神经系统。具体而言，我们将1)测试IL-22可溶性受体IL- 22BP和中和抗体的预防/治疗潜力，2)研究IL-22参与西尼罗河病毒发病的机制。如果成功，这些研究可能会导致预防西尼罗病毒感染的新策略。这种模式也适用于其他具有医学重要性的神经侵入性病毒病原体，如日本脑炎和圣路易斯脑炎病毒。

DESCRIPTION (provided by applicant): This proposal is to characterize the role of interleukin 22 (IL-22), a member of the IL-10-related cytokine family, in the pathogenesis of West Nile encephalitis using a mouse model. IL-22 has been implicated in both chronic inflammatory diseases and infectious diseases. On one hand, IL-22 contributes to pathogenesis of psoriasis and multiple sclerosis. On the other hand, IL-22 protects the liver from immune system-mediated damage during hepatitis, helps maintain epithelial barriers and induces secretion of anti-microbial peptides by the epithelia in response to extracellular pathogen infection, such as K. pneumoniae. However, to our best knowledge, the in vivo role of IL-22 in viral infections remains largely elusive. West Nile virus (WNV) is a neurotropic ssRNA flavivirus that has caused over 1000 deaths in the United States since 1999. However, no human vaccines or specific therapeutics are available. Interestingly we have recently shown that IL-22 does not influence the innate immune response and WNV propagation in the peripheral system, but facilitates the pathogenesis of West Nile encephalitis. We hereby propose to test the prophylactic/therapeutic potential of IL-22 antagonists and hypothesize that IL-22 promotes WNV entry into the central nervous system. Specifically we will 1) test the prophylactic/therapeutic potential of IL-22 soluble receptor IL- 22BP and neutralizing antibodies, and 2) Investigate the mechanism by which IL-22 contributes to WNV pathogenesis. If successful, these studies may lead to new strategies for the prevention of West Nile virus infection. This paradigm would also be applicable to other neuroinvasive viral pathogens of medical importance like Japanese encephalitis and Saint Louis encephalitis virus.