Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.02036-19.
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics of a febrile illness characterized by debilitating arthralgia and arthritis that can endure for months to years following infection. In mouse models, CHIKV persists in joint tissues for weeks to months and is associated with chronic synovitis. Using a recombinant CHIKV strain encoding a CD8 T cell receptor epitope from ovalbumin, as well as a viral peptide-specific major histocompatibility complex class I tetramer, we interrogated CD8 T cell responses during CHIKV infection. Epitope-specific CD8 T cells, which were reduced in and mice with known defects in antigen cross-presentation, accumulated in joint tissue and the spleen. Antigen-specific restimulation assays and killing assays demonstrated that CD8 T cells produce cytokine and have cytolytic activity. Despite the induction of a virus-specific CD8 T cell response, the CHIKV burden in joint-associated tissues and the spleen were equivalent in wild-type (WT) and CD8α mice during both the acute and the chronic phases of infection. In comparison, CD8 T cells were essential for the control of acute and chronic lymphocytic choriomeningitis virus infection in the joint and spleen. Moreover, adoptive transfer of virus-specific effector CD8 T cells or immunization with a vaccine that induces virus-specific effector CD8 T cells prior to infection enhanced the clearance of CHIKV infection in the spleen but had a minimal impact on CHIKV infection in the joint. Collectively, these data suggest that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading CD8 T cell immunity. CHIKV is a reemerging mosquito-transmitted virus that in the last decade has spread into Europe, Asia, the Pacific Region, and the Americas. Joint pain, swelling, and stiffness can endure for months to years after CHIKV infection, and epidemics have a severe economic impact. Elucidating the mechanisms by which CHIKV subverts antiviral immunity to establish and maintain a persistent infection may lead to the development of new therapeutic strategies against chronic CHIKV disease. In this study, we found that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading antiviral CD8 T cell immunity. Thus, immunomodulatory therapies that improve CD8 T cell immune surveillance and clearance of CHIKV infection could be a strategy for mitigating chronic CHIKV disease.
基孔肯雅热病毒（CHIKV）是一种经蚊子传播的甲病毒，可引起一种发热性疾病的爆发性流行，其特征是衰弱性关节炎和关节炎，感染后可持续数月至数年。在小鼠模型中，CHIKV 在关节组织中持续存在数周至数月，并与慢性滑膜炎有关。我们使用编码卵清蛋白 CD8 T 细胞受体表位的重组 CHIKV 株以及病毒肽特异性主要组织相容性复合体 I 四聚体，在感染 CHIKV 期间研究了 CD8 T 细胞反应。在抗原交叉呈递已知存在缺陷的 和 小鼠中，抗原特异性 CD8 T 细胞减少，在关节组织和脾脏中积累。抗原特异性再刺激试验和 杀伤试验表明，CD8 T 细胞产生细胞因子并具有细胞毒性活性。尽管诱导了病毒特异性 CD8 T 细胞反应，但在感染的急性期和慢性期，野生型（WT）和 CD8α 小鼠关节相关组织和脾脏中的 CHIKV 负荷均相等。相比之下，CD8 T 细胞对于控制急性和慢性淋巴细胞性脉络丛脑膜炎病毒在关节和脾脏中的感染是必不可少的。此外，在感染前通过过继转移病毒特异性效应 CD8 T 细胞或用诱导病毒特异性效应 CD8 T 细胞的疫苗进行免疫，增强了脾脏中 CHIKV 感染的清除，但对关节中 CHIKV 感染的影响最小。总的来说，这些数据表明，CHIKV 通过逃避 CD8 T 细胞免疫在关节相关组织中建立和维持持续性感染。CHIKV 是一种重新出现的经蚊子传播的病毒，在过去十年中已传播到欧洲、亚洲、太平洋地区和美洲。感染 CHIKV 后，关节疼痛、肿胀和僵硬可持续数月至数年，流行对经济造成严重影响。阐明 CHIKV 逃避抗病毒免疫以建立和维持持续性感染的机制，可能会导致针对慢性 CHIKV 疾病的新治疗策略的发展。在这项研究中，我们发现 CHIKV 通过逃避抗病毒 CD8 T 细胞免疫在关节相关组织中建立和维持持续性感染。因此，改善 CD8 T 细胞免疫监视和清除 CHIKV 感染的免疫调节疗法可能是减轻慢性 CHIKV 疾病的一种策略。
