PRJNA833593
Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation  and myelin loss in the brain
Survivors of COVID-19 frequently experience lingering neurological symptoms similar to the syndrome of cancer therapy-related cognitive impairment (CRCI). Here, we explored neuroinflammation caused by respiratory SARS-CoV-2 infection. Using a mouse model of mild respiratory SARS-CoV-2 infection, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Humans with COVID-19 exhibit the same pattern of white matter-enriched microglial reactivity. Pro-inflammatory CSF cytokines/chemokines were elevated in mice for at least 7-weeks-post-infection, including CCL11, a chemokine associated with impairments in neurogenesis and cognition. Systemic CCL11 administration causes microglial reactivity only in the hippocampus, together with impaired hippocampal neurogenesis. Humans experiencing long-COVID with cognitive symptoms similarly demonstrate elevated CCL11 levels compared to those without cognitive symptoms. Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident following mild respiratory SARS-CoV-2 infection in mice, consistent with the cellular deficits observed in CRCI. Comparing mouse models of mild respiratory infection with SARS-CoV-2 to H1N1 influenza, we found a similar pattern of white matter-selective microglial reactivity, oligodendrocyte loss, impaired hippocampal neurogenesis and elevated CSF CCL11 levels at one week. By 7-weeks after influenza, subcortical white matter microglial reactivity and oligodendrocytes normalize, while elevated CSF CCL11 levels persist together with lasting hippocampal white matter microglial reactivity and impaired neurogenesis. The findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to cognitive impairment following even mild COVID.