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

• 批准号: 9294901
• 负责人: Thomas E Morrison
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/9294901
• 关键词: 3-nitrotyrosine; Acute; Adoptive Transfer; 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; Geographic Locations; Human; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory; Injury; Interferons; Interleukin-10; Interleukin-6; Knock-out; Knowledge; Lesion; Link; Mediating; Mus; Musculoskeletal; Musculoskeletal Diseases; Musculoskeletal System; Myeloid Cells; Myositis; NOS2A gene; Nitrates; 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 disease; improved; inhibitor/antagonist; interleukin-10 receptor; macrophage; mouse model; novel therapeutic intervention; prevent; public health relevance; response; targeted treatment; vector mosquito

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）：引起关节炎的甲病毒，包括罗斯河病毒（RRV）和基孔肯雅病毒（CHIKV），是重新出现的蚊子传播甲病毒，可引起使人衰弱的肌肉骨骼炎症性疾病的地方性和爆炸性流行。南太平洋、非洲和亚洲发生了重大疫情，涉及数百万人。欧洲爆发的当地获得性 CHIKV 疾病以及感染 RRV 和 CHIKV 的旅行者返回包括美国在内的非流行地区，凸显了人们对这些病毒将继续传播到新地区的担忧。目前尚无治疗甲病毒引起的风湿病的特效疗法，也没有获得许可的疫苗。 RRV 和 CHIKV 感染的一个显着特征是，高达 64% 的感染者会出现慢性、失能的肌肉骨骼疾病，在人类和动物模型中，这种疾病与受影响组织的持续感染有关。因此，了解控制致关节炎甲病毒感染的免疫机制对于开发新的治疗策略至关重要。利用重现人类疾病重要方面的小鼠模型，我们在 RRV 和 CHIKV 感染小鼠的肌肉骨骼组织中检测到丰富的硝基酪氨酸（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) 和诱导型一氧化氮合酶 (iNOS; Nos2) 协同产生过氧亚硝酸盐，在感染 RRV 和 CHIKV 的小鼠以及骨髓细胞或缺乏 Arg1 的小鼠的炎症病变和组织浸润巨噬细胞中表达上调。 Nos2 表达减少了 RRV 感染后期的病毒载量和组织损伤，表明 Arg1 和 iNOS阻碍宿主对 RRV 感染的控制。其他初步数据表明，骨髓细胞 Arg1 作用于感染部位的 T 细胞，以限制病毒控制。基于这些数据，我们假设致关节炎甲病毒感染会在肌肉骨骼组织中诱导局部免疫抑制环境，从而促进持续感染和慢性疾病。我们建议定义 iNOS 和 Arg1 介导的过氧亚硝酸盐产生抑制 T 细胞反应的机制，并定义促进巨噬细胞免疫抑制活性的细胞因子信号传导途径，以防止控制肌肉骨骼组织中的 RRV 感染并促进慢性疾病。这些研究将明确 Arg1 和 iNOS 的作用以及调节其表达的信号通路在宿主控制急性和慢性关节炎性甲病毒感染和组织损伤中的作用，并将有助于开发新的宿主靶向治疗策略来治疗甲病毒引起的风湿病疾病。