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

白介素22在小鼠西尼罗病毒发病机制中的作用

• 批准号: 8444925
• 负责人: PENGHUA WANG
• 金额: $ 8.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444925
• 关键词: Animals; Antibodies; Blood; Blood - brain barrier anatomy; Brain; Calcium-Binding Proteins; Cardiovascular system; Cessation of life; Chlamydophila pneumoniae; Chronic; Communicable Diseases; Disease; Encephalitis; Epidemic; Epithelial; Epithelium; Family; Flavivirus; Hepatitis; Human; Immune response; Immune system; Infection; Infiltration; Inflammatory; Interleukin-10; Japanese Encephalitis; Klebsiella pneumonia bacterium; Lead; Leukocytes; Liver; Mediating; Medical; Multiple Sclerosis; Mus; Neuraxis; Pathogenesis; Peptides; Peripheral; Permeability; Population; Prevention strategy; Psoriasis; Resistance; Role; St. Louis Encephalitis Virus; System; Testing; Therapeutic; United States; Vaccines; Viral; Viral Load result; Viral load measurement; Virus Diseases; West Nile virus; antimicrobial; cell motility; cytokine; extracellular; in vivo; interleukin-22; member; mouse model; neurotropic; neutralizing antibody; neutrophil; pathogen; prophylactic; public health relevance; receptor; response; virus pathogenesis

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.

描述（由申请人提供）：本提案旨在使用小鼠模型来表征白介素 22（IL-22）（IL-10 相关细胞因子家族的成员）在西尼罗河脑炎发病机制中的作用。 IL-22 与慢性炎症性疾病和传染病有关。一方面，IL-22 有助于银屑病和多发性硬化症的发病机制。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，有助于维持上皮屏障并诱导上皮细胞分泌抗微生物肽，以应对细胞外病原体感染，例如肺炎克雷伯菌。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) 是一种嗜神经性 ssRNA 黄病毒，自 1999 年以来已在美国造成 1000 多人死亡。然而，目前还没有人类疫苗或特定治疗方法。有趣的是，我们最近发现 IL-22 不会影响先天免疫反应和 WNV 在外周系统中的传播，但会促进西尼罗河脑炎的发病机制。我们特此建议测试 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。具体来说，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，以及 2) 研究 IL-22 促进 WNV 发病机制的机制。如果成功，这些研究可能会带来预防西尼罗河病毒感染的新策略。这种范例也适用于其他具有医学重要性的神经侵袭性病毒病原体，例如日本脑炎和圣路易斯脑炎病毒。