Contributions of IRF5 to Chikungunya Viral Arthritis

项目总结/摘要 该提案的目标是将申请人发展成为一名独立的调查员， 一个研究自身免疫和抗病毒免疫交叉的项目。主要研究者（PI） 此前，他曾在生物化学和分子生物学博士培训，同时研究免疫 俄克拉荷马州医学研究基金会的白细胞运输机制。截至2015年，PI 完成了内科和风湿病学的临床培训，目前是博士后研究员 在圣刘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教授迈克尔·戴蒙德博士， 人类免疫学和免疫治疗项目中心主任， 先天免疫和病毒发病机制领域。戴蒙德博士有超过270篇具有特殊专长的出版物 在黄病毒的研究中（例如，西尼罗河病毒、登革热病毒和寨卡病毒）和甲病毒（例如，屈曲 病毒）。戴蒙德博士是一位传染病专家，他提供了一个成功的医生-科学家的典范。 申请人在华盛顿大学，一个国际公认的首要学术机构。 基孔肯雅病毒（CHIKV）是一种致关节炎的甲病毒，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年的岛屿CHIKV爆发表明，大多数感染CHIKV的患者进展为慢性CHIKV。 关节痛和关节炎。目前，特异性干扰素（IFN）刺激基因和转录的作用 CHIKV感染期间的因素仍在定义中。IFN调节因子（IRF）5是一种转录因子， 在病毒感染期间被激活，并且已知上调IFN刺激基因的表达，促进 促炎细胞因子的产生，并在某些条件下增强细胞凋亡。 导致人IRF 5过表达的多态性与发生以下疾病的风险相关： 系统性红斑狼疮和类风湿性关节炎。我们假设， CHIKV关节炎也可能与调节抗病毒免疫应答的IRF 5多态性有关 在急性感染期间。在这里，我们建议测试IRF 5表达的贡献，在全球和特定的细胞 使用已建立的CHIKV关节炎小鼠模型进行分型。我们还建议产生敲入小鼠， 异位表达IRF 5以测试IRF 5基因剂量对CHIKV关节炎发病机制的影响。使用 通过这些方法，申请人将获得免疫学、病毒学、自身免疫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相互作用。 遗传危险因素和病原体可能会引发慢性风湿病。

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.