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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的基孔肯雅病毒（CHIKV）是一种重新出现的甲病毒，最近通过其病毒传播到世界各地。该病毒极有可能在全世界范围内造成严重的发病率和死亡率，包括美国，佛罗里达州报告了首次传播，老年人对严重 CHIKV 特别敏感。疾病 (CHIKVD)，包括发烧、皮疹、关节疼痛，有时还累及实质器官（肝脏、大脑、肾脏）此外，CHIKVD 往往以多种形式持续存在于许多受试者中，尤其是老年受试者。当我们开始了解 CHIKV 时，关节炎/关节痛已持续数月甚至数年。发病机制和免疫方面，我们对年龄相关机制的了解还远远不够。 CHIKV 的脆弱性。我们最近开发了一种小鼠模型，它概括了在 CHIKV 中观察到的与年龄相关的临床结果- 感染老年人，并用它来开始阐明与年龄相关的功能障碍的机制我们发现 TGFβ 的增加，伴随着定性和免疫反应的增加。我们发现，B 细胞和 T 细胞反应的数量受损，无法清除病毒。抗体阻断可以预防与年龄相关的 CHIKV 疾病严重程度的增加，减少关节病理并提高中和抗体的产生，TGFβ也升高，中和抗体减少。患有 CHIKV 的老年人，使我们的模型可能与老年人直接相关。提议剖析导致 TGFβ 产生失调的机制，并阐明 TGFβ 是如何产生的我们的中心假设是，在古代 CHIKV 感染的小鼠，TGFβ 增加，通过作用调节针对 CHIKV 的 1 型 (T1) 免疫力依赖于可溶性因子、Th1、B 和可能的 Th17 细胞。假设将在以下目标中进行测试： SA1. 测试 T 细胞和 B 细胞内在和外在（环境）因素在次优状态下的作用。老年小鼠对 CHIKV 的适应性反应。 SA2. 检查升高的 TGFβ 是否以及如何直接作用于旧的适应性免疫细胞。这些实验将提供对 CHIKV 发病机制和免疫的详细见解并铺平道路针对老年人 CHIKVD/慢性关节炎的免疫干预方法。