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

摘要 基孔肯雅病毒(CHIKV)是一种新出现的甲型病毒，最近通过其 蚊子媒介。该病毒很有可能在世界范围内造成严重的发病率和死亡率，包括 美国，据报道，最初的传播是在佛罗里达州。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，有时还累及实质器官 (肝、脑、肾)。此外，CHIKVD倾向于在许多，特别是较老的受试者中以 严重衰弱的关节炎/关节痛，持续数月或数年。当我们开始了解CHIKV的时候 在发病机制和免疫方面，我们对年龄相关的机制还远远没有触及皮毛 CHIKV的漏洞。 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- 感染了老年人，并用它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。我们发现转化生长因子β的增加，伴随着定性和 B细胞和T细胞反应的数量受损，未能清除病毒。我们发现抗转化生长因子β 抗体阻断可阻止年龄相关性CHIKV疾病严重程度的增加，减轻关节病理 并提高中和抗体的产量。转化生长因子β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。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升高通过作用调节1型(T1)免疫紊乱 根据可溶性因子，Th1，B，也许还有Th17，细胞。这一假说及相关问题和分项 假设将在以下目标中得到检验： SA1.测试T和B细胞内在和外在(环境)因素在次优中的作用 老年小鼠对CHIKV的适应性反应。 SA2.研究升高的转化生长因子β是否以及如何直接作用于旧的获得性免疫细胞。 这些实验将对CHIKV和Pave的致病机理和免疫机制提供详细的见解 针对老年人CHIKVD/慢性关节炎的免疫干预方法。

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.