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

摘要 基孔肯雅病毒（CHIKV）是一种重新出现的甲病毒，最近通过其在世界各地传播。 蚊媒。该病毒很有可能在全世界造成严重的发病率和死亡率，包括 美国，最初的传播报告是在佛罗里达。老年人对严重的CHIKV特别敏感 疾病（CHIKVD），包括发热、皮疹、关节疼痛，有时累及实质器官 （肝、脑、肾）。此外，CHIKVD倾向于在许多受试者中，特别是老年受试者中，以CHIKVD的形式持续存在。 严重衰弱的关节炎/关节痛数月和数年。虽然我们开始了解CHIKV 发病机制和免疫，我们还远远没有触及表面上的机制与年龄有关 对CHIKV的脆弱性。 我们最近开发了一种小鼠模型，该模型概括了在CHIKV中观察到的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潜在机制， 对CHIKV感染的免疫反应。我们发现TGFβ的增加，伴随着定性和 未能清除病毒的B和T细胞应答的定量损伤。我们发现抗TGF β 抗体阻断可以防止年龄相关的CHIKV疾病严重程度的增加，减少关节病理学， 并提高中和抗体的产生。TGFβ也升高，中和抗体降低， 患有CHIKV的老年人，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。我们的核心假设是，在旧的 CHIKV感染的小鼠，通过作用增加TGFβ失调1型（T1）对CHIKV的免疫力 对可溶性因子Th 1、B和可能的Th 17细胞的影响。这个假设和相关的问题和子- 将在以下目标中检验假设： SA 1.为了测试T和B细胞-内在和外在（环境）因素在次最佳治疗中的作用， 老年小鼠对CHIKV的适应性反应。 SA 2.研究升高的TGFβ是否以及如何直接作用于老年适应性免疫细胞。 这些实验将提供对CHIKV的发病机制和免疫的详细见解，并为CHIKV的免疫提供基础。 免疫干预对老年人CHIKVD/慢性关节炎的方式。

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.