PDF(Pubmed)
Abstract：
Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed \"long COVID\". Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-γ correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals.
摘要：
主要是呼吸道感染,许多感染SARS-CoV-2的患者出现神经系统症状，一些在病毒清除后持续很长时间，作为一个持续的症状阶段，称为“长COVID”。高龄会增加严重疾病的风险，以及长期COVID的发病率。我们假设老年人免疫反应的扰动使老年人容易遭受严重的冠状病毒感染和感染后后遗症。使用呼吸道冠状病毒的鼠模型，小鼠肝炎病毒株A59（MHV-A59），我们发现衰老会增加临床疾病和对MHV感染的致死率，老年动物在急性感染期间大脑中携带的病毒增加。这与衰老动物脑内活化的CD8+T细胞的意外增加相关,但降低了这些CD8+T细胞的抗原特异性。老年动物在MHV感染后表现出空间学习障碍，这与衰老海马神经元细胞死亡增加和神经元再生减少有关。使用原代细胞培养，我们证明了活化的CD8+T细胞诱导神经元死亡，独立于抗原特异性。具体来说,较高水平的CD8+T细胞来源的IFN-γ与神经元死亡相关。这些结果支持以下证据：大脑中的CD8T细胞直接导致老年人冠状病毒感染后的认知功能障碍。
■使用小鼠呼吸道冠状病毒感染模型，我们发现,由于激活的CD8+T细胞在大脑中分泌IFN-γ,衰老会放大感染后认知功能障碍.这些数据提供了大脑中CD8+T细胞对感染后认知功能产生负面影响的证据。
■使用小鼠呼吸道冠状病毒感染模型，我们发现,由于激活的CD8+T细胞在大脑中分泌IFN-γ,衰老会放大感染后认知功能障碍.这些数据提供了大脑中CD8+T细胞对感染后认知功能产生负面影响的证据。
