Contributions of IRF5 to Chikungunya Viral Arthritis

IRF5 对基孔肯雅病毒性关节炎的贡献

• 批准号: 10541650
• 负责人: Jonathan J Miner
• 金额: $ 5.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-21 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541650
• 关键词: Contributions; IRF5; Chikungunya; Viral; Arthritis

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.

项目总结/文摘

项目成果

Regulation of cGAS and STING signaling during inflammation and infection.

• DOI: 10.1016/j.jbc.2023.104866
• 发表时间: 2023-07
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Chauvin, Samuel D.;Stinson, W. Alexander;Platt, Derek J.;Poddar, Subhajit;Miner, Jonathan J.
• 通讯作者: Miner, Jonathan J.

STING-associated vasculopathy develops independently of IRF3 in mice.

• DOI: 10.1084/jem.20171351
• 发表时间: 2017-11-06
• 期刊: The Journal of experimental medicine
• 作者: Warner JD;Irizarry-Caro RA;Bennion BG;Ai TL;Smith AM;Miner CA;Sakai T;Gonugunta VK;Wu J;Platt DJ;Yan N;Miner JJ
• 通讯作者: Miner JJ

Consequences of congenital Zika virus infection.

先天性寨卡病毒感染的后果。

• DOI: 10.1016/j.coviro.2017.09.005
• 发表时间: 2017
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Platt,DerekJ;Miner,JonathanJ
• 通讯作者: Miner,JonathanJ

Lesion evolution and neurodegeneration in RVCL-S: A monogenic microvasculopathy.

• DOI: 10.1212/wnl.0000000000010659
• 发表时间: 2020-10-06
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Ford AL;Chin VW;Fellah S;Binkley MM;Bodin AM;Balasetti V;Taiwo Y;Kang P;Lin D;Jen JC;Grand MG;Bogacki M;Liszewski MK;Hourcade D;Chen Y;Hassenstab J;Lee JM;An H;Miner JJ;Atkinson JP
• 通讯作者: Atkinson JP

The IFN-γ receptor promotes immune dysregulation and disease in STING gain-of-function mice.

• DOI: 10.1172/jci.insight.155250
• 发表时间: 2022-09-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Stinson, W. Alexander;Miner, Cathrine A.;Zhao, Fang R.;Lundgren, Annena Jane;Poddar, Subhajit;Miner, Jonathan J.
• 通讯作者: Miner, Jonathan J.