Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection.
Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection.
复制标题
抗原非特异性 CD8 T 细胞加速老年小鼠呼吸道冠状病毒感染后认知能力的下降。
DOI：
10.1101/2024.01.02.573675
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Funk,KristenE
中科院分区：
文献类型：
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作者：
Reagin,KatieL;Lee,Rae-Ling;Cocciolone,Loren;Funk,KristenE
SARS-CoV-2主要是一种呼吸道感染，许多感染SARS-CoV-2的患者出现神经系统症状，其中一些人在病毒清除后很长一段时间仍在持续，这一症状被称为“长冠状病毒病”。高龄会增加患严重疾病的风险，也会增加慢性冠状病毒感染的发生率。我们假设，老年人免疫反应的紊乱使老年人容易受到严重的冠状病毒感染和感染后的后遗症。使用呼吸道冠状病毒小鼠模型，小鼠肝炎病毒株A59(MHV-A59)，我们发现年龄增加了临床疾病和对MHV感染的致死率，老年动物在急性感染期间大脑中的病毒增加。此外，老年动物大脑中激活的CD8+T细胞意外增加，但这些CD8+T细胞的抗原特异性降低。老年动物在MHV感染后表现出空间学习障碍，这与老年海马神经细胞死亡增加和神经元再生减少有关。利用原代细胞培养，我们证明了激活的CD8+T细胞诱导神经元死亡，而不是抗原特异性的。具体地说，CD8+T细胞来源的干扰素-γ水平较高与神经元死亡相关。这些结果支持了脑中CD8+T细胞直接导致老年人冠状病毒感染后认知功能障碍的证据。
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.