Mechanisms of immune suppression during arthritogenic alphavirus infections

致关节炎甲病毒感染期间的免疫抑制机制

基本信息

批准号：
8757434
负责人：
Thomas E Morrison
金额：
$ 38.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8757434
关键词：
3-nitrotyrosine Acute Affect Africa Alphavirus Alphavirus Infections Animal Model Area Arthritis Asia CD44 gene Chikungunya virus Chronic Chronic Disease Culicidae Cytokine Signaling Data Development Disease Disease Outbreaks Employee Strikes Environment Enzymes Epidemic Europe Genetic Human Immune response Immunosuppression Immunosuppressive Agents Individual Infection Inflammation Inflammatory Injury Interferons Interleukin-10 Interleukin-6 Knock-out Knowledge Lesion Licensing Link Mediating Mus Musculoskeletal Musculoskeletal Diseases Musculoskeletal System Myeloid Cells Myositis Oxidants Pain Pathogenesis Pathology Pathway interactions Peroxonitrite Persons Play Population Production Proteins Regulation Regulatory T-Lymphocyte Rheumatism Rheumatoid Arthritis Risk Role Ross river virus Series Severity of illness Signal Pathway Signal Transduction Site Southeastern United States Stress T cell response T-Cell Depletion T-Lymphocyte Testing Therapeutic Time Tissues United States Vaccines Viral Viral Antigens Viral Load result Viral load measurement Virus Virus Diseases arginase base cytokine human NOS2A protein human disease improved inhibitor/antagonist macrophage mouse model novel therapeutics prevent public health relevance receptor therapeutic target vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are re-emerging, mosquito-transmitted alphaviruses that cause both endemic and explosive epidemics of debilitating musculoskeletal inflammatory disease. Major outbreaks have occurred in the South Pacific, Africa, and Asia involving millions of persons. Locally-acquired CHIKV disease outbreaks in Europe and the return of RRV and CHIKV-infected travelers to nonendemic regions, including the United States, has highlighted concern that these viruses will continue to spread to new areas. There are no specific therapies for the treatment of alphavirus-induced rheumatological disease and no licensed vaccines. A striking feature of RRV and CHIKV infections is the development of chronic, incapacitating musculoskeletal disease in up to 64% of infected individuals, which has been linked in both humans and animal models to persistent infection in the affected tissues. Thus, understanding the immunological mechanisms that control arthritogenic alphavirus infection is essential for the development of new therapeutic strategies. Utilizing mouse models that recapitulate important aspects of human disease, we detected abundant nitrotyrosine, a marker of peroxynitrite activity, in the musculoskeletal tissues of RRV- and CHIKV-infected mice. Peroxynitrite is a potent inducer of nitrative stress that causes tissue damage and suppresses T cell responses. Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS; Nos2), enzymes that synergize to produce peroxynitrite, were upregulated in inflammatory lesions and tissue-infiltrating macrophages of RRV- and CHIKV-infected mice, and mice lacking Arg1 in myeloid cells or Nos2 expression had reduced viral loads and tissue damage at late times post-RRV infection, indicating that Arg1 and iNOS thwart host control of RRV infection. Additional preliminary data suggests that myeloid cell Arg1 acts on T cells at the sites of infection to limit virus control. Based on these data, we hypothesize that arthritogenic alphavirus infection induces a localized immunosuppressive environment in musculoskeletal tissues that promotes persistent infection and chronic disease. We propose to define mechanisms by which iNOS and Arg1-mediated production of peroxynitrite suppresses T cell responses, and to define the cytokine signaling pathways that promote the immunosuppressive activity of macrophages, to prevent control of RRV infection in musculoskeletal tissues and promote chronic disease. These studies will define the role of Arg1 and iNOS, and signaling pathways that regulate their expression, in host control of acute and chronic arthritogenic alphavirus infection and tissue injury and will aid the development of new host-targeted therapeutic strategies to treat alphavirus-induced rheumatological disease.

描述（由申请人提供）：包括罗斯河病毒（RRV）和Chikungunya病毒（Chikv）在内的关节炎α病毒，正在重新出现，蚊子传播的α病毒引起肌肉肌肉骨骼炎性疾病的流行性和爆炸性流行病。南太平洋，非洲和亚洲发生了重大暴发，涉及数百万人。欧洲当地获得的CHIKV疾病爆发以及RRV和CHIKV感染的旅行者返回包括美国在内的非流行地区，强调了这些病毒将继续传播到新地区。没有特定的疗法用于治疗α病毒诱导的风湿病疾病，也没有执照的疫苗。 RRV和CHIKV感染的一个惊人特征是，多达64％的受感染个体的慢性，无能为力的肌肉骨骼疾病的发展，这些受感染的个体和动物模型都与受影响组织中的持续感染联系在一起。因此，了解控制关节性α病毒感染的免疫机制对于发展新的治疗策略至关重要。利用小鼠模型概括了人类疾病的重要方面，我们检测到了RRV和CHIKV感染的小鼠的肌肉骨骼组织中丰富的亚硝基酪氨酸（过氧亚硝酸盐活性的标志物）。过氧亚硝酸盐是硝化应激的有效诱导剂，会导致组织损伤并抑制T细胞反应。精氨酸酶1（ARG1）和诱导型一氧化氧化物合酶（INOS; NOS2），协同产生过氧亚硝酸盐的酶在炎症性病变和组织浸润的巨噬细胞中被上调RRV后感染，表明ARG1和INOS TRAT宿主对RRV感染的控制。其他初步数据表明，髓样细胞ARG1在感染部位作用于T细胞，以限制病毒控制。基于这些数据，我们假设关节炎α病毒感染在肌肉骨骼组织中诱导局部免疫抑制环境，从而促进持续性感染和慢性疾病。我们建议定义iNOS和ARG1介导的过氧亚硝酸盐产生的机制，可抑制T细胞反应，并定义促进巨噬细胞免疫抑制活性的细胞因子信号通路，以防止控制肌肉骨骼组织中RRV感染的控制，并促进慢性病。这些研究将定义ARG1和INOS的作用，以及调节其表达的信号传导途径，在宿主控制急性和慢性关节性α病毒感染和组织损伤中，并将有助于发展新的宿主治疗策略，以治疗α病毒诱导的流变学疾病。