Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Department of Immunobiology, Yale University, New Haven, CT, USA.
Cell. 2022 Jul 7;185(14):2452-2468.e16. doi: 10.1016/j.cell.2022.06.008. Epub 2022 Jun 13.
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
COVID 幸存者经常出现类似于癌症治疗相关认知障碍的挥之不去的神经症状，这种综合征的核心是白质小胶质细胞反应和随之而来的神经调节紊乱。在这里，我们探讨了呼吸 SARS-CoV-2 感染的神经生物学效应，发现在小鼠和人类中存在白质选择性小胶质细胞反应。在小鼠轻度呼吸 COVID 后，明显存在持续受损的海马神经发生、少突胶质细胞减少和髓鞘丢失，同时伴有脑脊液细胞因子/趋化因子水平升高，包括 CCL11。系统性 CCL11 给药特异性引起海马小胶质细胞反应和神经发生受损。一致地，COVID 后持续存在认知症状的患者表现出 CCL11 水平升高。与 SARS-CoV-2 相比，小鼠轻度呼吸性流感在早期也引起了类似的白质选择性小胶质细胞反应、少突胶质细胞丢失、神经发生受损和 CCL11 升高模式，但流感后仅 CCL11 和海马病理学持续存在。这些发现说明了癌症治疗和呼吸 SARS-CoV-2 感染后的类似神经病理学，这可能导致即使是轻度 COVID 后也会出现认知障碍。
