Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV)

基孔肯雅病毒（CHIKV）与年龄相关的易感性机制

• 批准号: 10436970
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 33.77万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436970
• 关键词: Ablation; Acute; Adult; African; Aging; Alphavirus; Antibodies; Antibody Formation; Arthralgia; Arthritis; Asian; B-Lymphocytes; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Caribbean region; Cells; Cessation of life; Chikungunya virus; Chronic; Clinical; Color; Country; Defect; Disease; Elderly; Environment; Environmental Risk Factor; Epidemic; Exanthema; Exhibits; Exposure to; Fever; Florida; Genetic; Human; Immune; Immune System Diseases; Immune response; Immunity; Impairment; In Situ Hybridization; Individual; Infection; Inflammation; Inflammatory; Interferon-alpha; Interleukin-17; Joints; Kidney; Knockout Mice; Lead; Liver; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Organ; Organism; Outcome; Pathogenesis; Pathogenicity; Pathology; Population; Predisposition; Production; Regulation; Reporter; Reporting; Risk; Risk Factors; Role; Serum; Severity of illness; Signal Transduction; Surface; T cell response; T-Lymphocyte; Testing; Transforming Growth Factor beta; Viral; Viral Pathogenesis; Virus; Virus Diseases; Wild Type Mouse; adaptive immune response; age related; chikungunya infection; cytokine; experimental study; immunological intervention; immunopathology; improved; insight; joint inflammation; macrophage; mature animal; mortality; mosquito-borne; mouse model; neutralizing antibody; prevent; response; tool; transmission process; vector mosquito; viral resistance; young adult

Abstract Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV disease (CHIKVD), which includes fever, rash, joint pain and sometimes involvement of parenchymal organs (liver, brain, kidney). Moreover, CHIKVD tends to persist in many, particularly older, subjects in the form of highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related vulnerability to CHIKV. We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV- infected elderly humans, and used it to begin to elucidate mechanisms underlying the age-related dysfunction of the immune response to CHIKV infection. We found an increase in TGFβ, concomitant with qualitative and quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGFβ antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology and improve production of neutralizing antibodies. TGFβ was also elevated and neutralizing Ab reduced in older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we propose to dissect mechanisms that lead to dysregulated TGFβ production and to elucidate how TGFβ contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in old CHIKV-infected mice, increased TGFβ dysregulates type 1 (T1) immunity against CHIKV by acting upon soluble factors, Th1, B and perhaps Th17, cells. This hypothesis and related questions and sub- hypotheses will be tested in the following Aims: SA1. To test the roles of T and B cell-intrinsic and extrinsic (environmental) factors in suboptimal adaptive responses of old mice to CHIKV. SA2. To examine whether and how elevated TGFβ acts directly on old adaptive immune cells. These experiments will provide detailed insights into pathogenesis and immunity against CHIKV and pave the way for immune interventions against CHIKVD/chronic arthritis in older adults.

抽象的 Chikungunya病毒（Chikv）是一种重新出现的α病毒，最近通过其散布在世界各地 蚊子向量。该病毒在全球范围内具有很高的发病率和死亡率的潜力很高，包括 美国，佛罗里达州的最初传输报道。老年人对严重的chikv特别敏感 疾病（CHIKVD），其中包括发烧，皮疹，关节疼痛以及有时会涉及副型器官 （肝脏，脑，肾脏）。而且，Chikvd倾向于以许多形式的人（尤其是较旧的主题）持续存在 高度使人衰弱的关节炎/关节痛数月和几年。当我们开始理解chikv时 发病机理和免疫力，我们甚至还没有在与年龄相关的机理上刮擦表面 Chikv的脆弱性。 我们最近开发了一种小鼠模型，该模型概括了Chikv-中观察到的与年龄有关的临床结果。 感染了人类，并用它开始阐明与年龄相关功能障碍的基础机制 对CHIKV感染的免疫反应。我们发现TGFβ有所增加，与定性和 B和T细胞反应中未能清除病毒的定量损伤。我们表明抗TGFβ 抗体阻滞可以防止Chikv疾病严重程度与年龄相关的增加，减少关节病理 并改善了中和抗体的产生。 TGFβ还升高并中和AB减少 年龄较大的人患有CHIKV，使我们的模型可能与老年人直接相关。在这里，我们 提议剖析导致TGFβ产生失调并阐明TGFβ的机制 有助于增加病理学和增加CHIKV控制。我们的中心假设是在古老 CHIKV感染的小鼠，TGFβ失调1型（T1）免疫组织化学对CHIKV的影响通过作用 在固体因素上，Th1，B，也许是Th17细胞。这个假设及相关问题以及子 假设将在以下目的中进行检验： SA1。测试T和B细胞中心和外部（环境）因子在次优的角色的作用 老鼠对Chikv的自适应反应。 SA2。检查TGFβ是否以及如何直接在旧适应性免疫细胞上作用。 这些实验将提供有关针对Chikv和Cave的发病机理和免疫力的详细见解 针对老年人CHIKVD/慢性关节炎的免疫干预措施的方法。