Contributions of IRF5 to Chikungunya Viral Arthritis

项目摘要/摘要 这项提议的目标是将申请者发展成为一名具有研究能力的独立调查者 研究自身免疫和抗病毒免疫交集的程序。首席调查员(PI) 之前在学习免疫学时接受了生物化学和分子生物学的博士培训 俄克拉荷马医学研究基金会的白细胞转移机制。截至2015年，PI拥有 完成内科及风湿病临床训练，现为博士后 在圣路易斯的华盛顿大学接受免疫学和病毒学的正式培训。 导师是华盛顿大学医学副教授迈克尔·戴蒙德博士 人类免疫学和免疫疗法项目中心主任，也是 先天免疫和病毒发病机制的研究领域。《戴蒙德博士》拥有270多份具有特殊专业知识的出版物 在研究黄病毒(例如西尼罗河病毒、登革热病毒和寨卡病毒)和甲型病毒(例如基孔肯雅病毒)时 病毒)。戴蒙德博士是一位传染病专家，他提供了一个成功的内科科学家的典范 申请人在华盛顿大学，国际公认的一流学术机构。 基孔肯雅病毒(CHIKV)是一种致关节炎的甲型病毒，可引起急性和慢性滑膜炎。 类似血清阴性类风湿性关节炎的分布。团聚后进行的流行病学研究 2006年爆发的岛屿CHIKV表明，大多数感染CHIKV的患者进展为慢性 关节痛和关节炎。目前，特异性干扰素(干扰素)刺激基因和转录的作用 CHIKV感染过程中的因素仍在确定中。干扰素调节因子(IRF)5是一种转录因子 在病毒感染过程中被激活，已知可以上调干扰素刺激基因的表达，促进 产生促炎细胞因子，并在一定条件下促进细胞凋亡。 导致人类IRF5过度表达的基因多态与发病风险相关 系统性红斑狼疮和类风湿性关节炎。我们假设病毒的严重性和持续时间 CHIKV关节炎也可能与调节抗病毒免疫反应的IRF5基因多态性有关 在急性感染期间。在这里，我们建议测试IRF5在全球和特定细胞中的表达贡献 使用已建立的CHIKV关节炎小鼠模型进行分型。我们还建议制造一种基因敲入的小鼠 异位表达IRF5，检测IRF5基因剂量对CHIKV关节炎发病机制的影响。vbl.使用 通过这些方法，申请者将获得免疫学、病毒学、自身免疫学和病毒性关节炎方面的专业知识。 这将为一个独立的研究项目奠定基础，该项目将研究宿主之间的互动 可能引发慢性风湿病的遗传风险因素和病原体。

Project Summary/Abstract The goal of this proposal is to develop the applicant into an independent investigator with a research program that examines the intersection of autoimmunity and antiviral immunity. The principal investigator (PI) previously received his PhD training in biochemistry and molecular biology while studying immune mechanisms of leukocyte trafficking at the Oklahoma Medical Research Foundation. As of 2015, the PI has completed his clinical training in internal medicine and rheumatology and is currently a post-doctoral fellow receiving formal training in immunology and virology at Washington University in Saint Louis. The mentor is Dr. Michael Diamond, Professor of Medicine at Washington University, Associate Director of the Center for Human Immunology and Immunotherapy Programs, and an established leader in the fields of innate immunity and viral pathogenesis. Dr. Diamond has over 270 publications with special expertise in studies of flaviviruses (e.g., West Nile, Dengue, and Zika viruses) and alphaviruses (e.g., Chikungunya virus). Dr. Diamond is an infectious disease specialist who provides a model of a successful physician-scientist to the applicant at Washington University, an internationally recognized premier academic institution. Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes acute and chronic synovitis in a distribution that mimics seronegative rheumatoid arthritis. Epidemiological studies conducted after the Reunion Island CHIKV outbreak in 2006 suggest that a majority of patients infected with CHIKV progress to chronic arthralgias and arthritis. At present, the role of specific interferon (IFN) stimulated genes and transcription factors during CHIKV infection is still being defined. IFN regulatory factor (IRF)5 is a transcription factor that is activated during viral infection and is known to upregulate expression of IFN stimulated genes, promote production of proinflammatory cytokines, and enhance apoptosis under certain conditions. Polymorphisms resulting in overexpression of human IRF5 are associated with the risk of developing systemic lupus erythematosus and rheumatoid arthritis. We hypothesize that the severity and duration of CHIKV arthritis also may be related to IRF5 polymorphisms that modulate the antiviral immune response during acute infection. Here, we propose to test the contribution of IRF5 expression globally and in specific cell types using an established mouse model of CHIKV arthritis. We also propose to generate knock-in mice that ectopically express IRF5 to test the effect of IRF5 gene dosage on the pathogenesis of CHIKV arthritis. Using these approaches, the applicant will gain expertise in immunology, virology, autoimmunity, and viral arthritis. This will establish a foundation for an independent research program that will study interactions between host genetic risk factors and pathogens that may act to trigger chronic rheumatologic diseases.