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

基孔肯雅病毒(CHIKV)是最近在世界范围内传播的一种新出现的甲型病毒 通过它的蚊子媒介。该病毒极有可能造成严重的发病率和死亡率。 包括美国在内的世界各地，据报道最初的传播是在佛罗里达州。老年人尤其是 对严重的CHIKV疾病(CHIKVD)敏感，包括发烧、皮疹、关节疼痛，有时 实质器官(肝、脑、肾)受累。此外，CHIKVD倾向于在许多地方持续存在， 尤其是年龄较大的受试者，会出现几个月甚至几年的高度衰弱的关节炎/关节痛的形式。而当 我们开始了解CHIKV的发病机制和免疫，我们甚至远远没有抓到 关于与年龄有关的CHIKV易感性的机制。 我们最近开发了一种小鼠模型，它概括了与年龄相关的临床结果。 在感染CHIKV的老年人中观察到的，并用它开始阐明潜在的机制 CHIKV感染所致免疫反应的年龄相关性功能障碍。我们发现产量下降了 CXCL9的表达和转化生长因子β的增加，伴随着B和T质和量的损害 未能清除病毒的细胞反应。我们发现抗转化生长因子β抗体阻断可以 预防增龄性CHIKV疾病严重程度增加，减轻关节病理改善 产生中和抗体。老年患者转化生长因子β也升高，中和抗体降低 人类患有CHIKV，这使得我们的模型可能与老年人直接相关。在这里，我们 建议解剖导致转化生长因子β产生失调的机制，并阐明转化生长因子β是如何 有助于增加病理和降低CHIKV控制。我们的中心假设是，在旧的 CHIKV感染小鼠、转化生长因子β增加和CXCL9水平降低相互作用和/或协同作用 通过作用于Th1、B和Treg细胞来调节对CHIKV的免疫。这一假设和 相关问题和次级假设将在以下目标中进行检验： 目的1.测试适应性免疫中与年龄相关的缺陷是否以及如何有助于 免疫病理学，CHIKV控制不佳，或两者兼而有之。 目的2.阐明转化生长因子β在CHIKV感染过程中如何以及为什么会随着年龄的增长而失控。 目的3.明确转化生长因子β如何损害获得性免疫CHIKV并使关节沉淀 随年龄增长的病理变化。 这些实验将对CHIKV的发病机制和免疫机制提供详细的见解。 在老年生物体中，为老年人CHIKVD/慢性关节炎的免疫干预铺平了道路。

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 decreased production of CXCL9 and 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 in old CHIKV-infected mice, increased TGFβ and reduced CXCL9 levels interact and/or synergistically dysregulate immunity against CHIKV by acting upon Th1, B and Treg cells. This hypothesis and related questions and sub-hypotheses will be tested in the following Aims: Aim 1. To test whether and how age-related defects in adaptive immunity contribute to immunopathology, poor CHIKV control or both. Aim 2. To elucidate how and why TGFβ is dysregulated with aging during CHIKV infection. Aim 3. To define how TGFβ impairs adaptive immunity CHIKV and precipitates joint pathology with age. These experiments will provide detailed insights into pathogenesis and immunity against CHIKV in old organisms, paving way for immune interventions against CHIKVD/chronic arthritis in older adults.