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

基孔肯雅病毒（CHIKV）是一种重新出现的甲病毒，最近在世界各地蔓延 通过蚊子传播该病毒有很高的潜力造成重大的发病率和死亡率 包括美国在内的世界各地，最初的传播报告是在佛罗里达。老年人尤其 对严重的CHIKV疾病（CHIKVD）敏感，包括发热、皮疹、关节疼痛，有时 累及实质器官（肝、脑、肾）。此外，CHIKVD倾向于在许多， 特别是老年人，以数月和数年的高度衰弱性关节炎/关节痛的形式。而 我们开始了解CHIKV的发病机制和免疫，我们甚至还远未触及 表面上的机制与年龄相关的脆弱性CHIKV。 我们最近开发了一种小鼠模型，该模型概括了与年龄相关的临床结果。 在CHIKV感染的老年人中观察到，并使用它来开始阐明潜在的机制 对CHIKV感染的免疫应答的年龄相关功能障碍。我们发现产量下降 CXCL 9的表达和TGFβ的增加，伴随着B和T的定性和定量损伤 无法清除病毒的细胞反应。我们发现，抗TGF β抗体阻断可以 预防CHIKV疾病严重程度的年龄相关性增加，减少关节病理学，并改善 中和抗体的产生。老年组TGFβ也升高，中和抗体降低， 患有CHIKV的人类，使我们的模型可能与老年人直接相关。这里我们 我建议剖析导致TGFβ产生失调的机制，并阐明TGFβ 导致病理学增加和CHIKV控制降低。我们的中心假设是，在旧的 CHIKV感染的小鼠，增加的TGFβ和降低的CXCL 9水平相互作用和/或协同作用 通过作用于Th 1、B和Treg细胞来失调针对CHIKV的免疫。这个假设和 相关问题和子假设将在以下目标中进行检验： 目标1。为了测试是否以及如何与年龄相关的适应性免疫缺陷有助于 免疫病理学、差的CHIKV控制或两者。 目标二。为了阐明在CHIKV感染期间TGFβ如何以及为什么随着衰老而失调。 目标3。为了确定TGFβ如何损害获得性免疫CHIKV和沉淀关节炎， 病理随着年龄的增长 这些实验将为CHIKV的发病机制和免疫提供详细的见解 在老年生物体中，为老年人中针对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.