The role of type I interferons during chikungunya virus infection

I型干扰素在基孔肯雅病毒感染过程中的作用

• 批准号: 10066091
• 负责人: Marissa Christine Locke
• 金额: $ 3.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066091
• 关键词: Acute; Acute Disease; Address; Aedes; Africa; Alphavirus; Animal Model; Antiviral Agents; Antiviral Therapy; Apoptotic; Arthralgia; Arthritis; Arthritogenic; Caribbean region; Cells; Central America; Chikungunya virus; Chronic; Chronic Disease; Culicidae; Data; Disease; Exanthema; Fever; Fibroblasts; Florida; Follow-Up Studies; Genes; Genetic Transcription; Histologic; IFNAR1 gene; In Vitro; Indian Ocean; Individual; Infection; Inflammation; Innate Immune System; Integration Host Factors; Interferon Receptor; Interferon Type I; Interferon-beta; Interferons; Intramuscular; Joints; Knowledge; Lead; Macaca; Mediating; Monoclonal Antibodies; Mus; Muscle; Muscle Cells; Muscle satellite cell; Musculoskeletal; Musculoskeletal Diseases; Myalgia; North America; Pathogenesis; Pathogenicity; Patients; Play; Population; RNA; Recovery; Reporter; Reporting; Role; Signal Transduction; South America; Symptoms; Synovial Fluid; System; Testing; Texas; Time; Type I Epithelial Receptor Cell; United States; Vaccines; Viral; Viral Arthritis; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; acute infection; cell type; chikungunya infection; combat; cytokine; effective therapy; immunopathology; immunoregulation; in vivo; mouse model; neutrophil; novel; pathogen; receptor; response; satellite cell; tool; transcriptome sequencing; transmission process; treatment strategy; viral RNA

Project Summary Chikungunya virus (CHIKV) is a single-stranded RNA arthritogenic alphavirus and an emerging mosquito- transmitted pathogen. Acute CHIKV symptoms include rash, fever, arthritis, arthralgias, and myalgias. Since 2013, more than 1.9 million cases have been reported throughout the Caribbean, Central, and South America. Following recovery from acute CHIKV disease, chronic muscle and joint symptoms can persists 60% of patients. Replicating CHIKV is not detected during chronic time points. Yet, histological changes and noninfectious CHIKV RNA has been detected in patients and animal models. Unfortunately, tools to study chronic CHIKV have been inadequate to elucidate the cause of disease and are too insensitive to visualize the cells harboring persistent CHIKV RNA. In addition, the host factors that contribute to this chronic disease are largely unknown. As no specific antiviral therapies or vaccines for CHIKV exist, further understanding of host and viral factors that mediate acute and chronic CHIKV is crucial to combat this virus. Type I interferons (IFNs) are major effector cytokines of the innate immune system and include 14 IFN subtypes, IFN, and others. All type I IFNs signal through the shared heterodimeric IFN/ receptor to elicit antiviral, anti-proliferative, pro-apoptotic, or immunomodulatory effects. Previous work demonstrated that type I IFNs are robustly induced during both acute and chronic CHIKV infection in vivo and are necessary for protection. Despite signaling through a single, shared receptor, IFN subtypes have distinct potencies in vitro and differential functions in vivo. We have found that during acute disease, mice lacking IFN or IFN are more susceptible to acute CHIKV-induced disease. IFN limits viral replication and dissemination of CHIKV while IFN limits inflammation mediated by neutrophils. In both cases, these actions are mediated by signaling on nonhematopoietic cells. Yet, the cell types upon which type I IFNs act, the mechanistic correlates of protection, and whether IFN and IFN play a role during chronic disease remain uncertain. The proposed aims will determine the mechanistic basis of differential type I IFN protection or pathogenicity during acute CHIKV and the actions of the various subtypes during chronic disease. Therefore, we propose to use various Cre expressing mice and a mouse model of CHIKV to delete the type I IFN receptor on muscle cells, muscle satellite cells, or fibroblasts and examine acute pathogenesis and attempt to elucidate how the type I IFN subtypes mediate their differential effects during acute disease. In addition, we propose to study the impact of the type I IFN subtypes on chronic CHIKV inflammation, persistent RNA, and the cells that survive acute infection using our novel reporter system. Overall, the proposed work will address numerous gaps in current knowledge: which nonhematopoietic cells are important for type I IFN-mediated protection from CHIKV, how cells that have survived acute infection contribute to chronic pathogenesis, and the roles of specific type I IFN subtypes during chronic disease. These findings could inform treatment options for CHIKV patients suffering from chronic musculoskeletal inflammation.

项目摘要 Chikungunya病毒（Chikv）是一种单链RNA关节型α病毒和新兴的蚊子 - 传播病原体。急性CHIKV症状包括皮疹，发烧，关节炎，关节痛和肌痛。自从 2013年，整个加勒比海，中央和南美都有超过190万例案件。 从急性CHIKV疾病中恢复后，慢性肌肉和关节症状可以持续60％的患者。 在慢性时点未检测到复制CHIKV。然而，组织学变化和非感染的chikv 在患者和动物模型中已检测到RNA。不幸的是，研究慢性chikv的工具已经 不足以阐明疾病的原因，并且不敏感，无法可视化具有持续的细胞 chikv RNA。此外，导致这种慢性疾病的宿主因素在很大程度上尚不清楚。否 存在特定的抗病毒疗法或CHIKV的疫苗，对宿主和病毒因素的进一步了解 介导的急性和慢性CHIKV对于对抗该病毒至关重要。 I型干扰素（IFN）是主要效应器 先天免疫系统的细胞因子，包括14个IFN亚型，IFN等。所有类型I IFNS信号 通过共享的异二聚体IFN/受体引起抗病毒，抗增殖，促凋亡或 免疫调节作用。以前的工作证明了I型IFN在两个急性期间都有强烈的诱导 体内慢性CHIKV感染是必要的。尽管通过单个发出信号，但共享 接收器，IFN亚型在体内具有不同的体外和差异功能。我们发现 在急性疾病期间，缺乏IFN或IFN的小鼠更容易受到急性CHIKV诱导的疾病的影响。 ifn 限制了CHIKV的病毒复制和传播，而IFN限制了中性粒细胞介导的炎症。在 两种情况下，这些作用均通过对非hematopoietic细胞的信号传导介导。但是，细胞类型 I型IFNS ACT，保护的机械相关性以及IFN和IFN是否在慢性期间起作用 疾病仍然不确定。提出的目标将确定I型I型的机械基础 急性CHIKV期间的IFN保护或致病性以及在 慢性病。因此，我们建议使用各种表达小鼠的CRE和CHIKV的小鼠模型 删除肌肉细胞，肌肉卫星细胞或成纤维细胞上的I型IFN受体并检查急性 发病机理和试图阐明I型IFN亚型如何介导急性效果的差异作用 疾病。此外，我们建议研究I型IFN亚型对慢性CHIKV炎症的影响， 持续的RNA以及使用我们的新报告基因系统生存急性感染的细胞。总体而言，提议 工作将解决当前知识中的许多差距：哪些非杂质细胞对于I型很重要 IFN介导的保护免受CHIKV的保护，在急性感染中幸存的细胞如何有助于慢性 发病机理以及特异性I型IFN亚型在慢性疾病中的作用。这些发现可以告知 患有慢性肌肉骨骼炎症的CHIKV患者的治疗选择。