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Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

ABSTRACT: 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.

SUBMITTER: Fernandez-Castaneda A

PROVIDER: S-EPMC9189143 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

Fernández-Castañeda Anthony A Lu Peiwen P Geraghty Anna C AC Song Eric E Lee Myoung-Hwa MH Wood Jamie J O'Dea Michael R MR Dutton Selena S Shamardani Kiarash K Nwangwu Kamsi K Mancusi Rebecca R Yalçın Belgin B Taylor Kathryn R KR Acosta-Alvarez Lehi L Malacon Karen K Keough Michael B MB Ni Lijun L Woo Pamelyn J PJ Contreras-Esquivel Daniel D Toland Angus Martin Shaw AMS Gehlhausen Jeff R JR Klein Jon J Takahashi Takehiro T Silva Julio J Israelow Benjamin B Lucas Carolina C Mao Tianyang T Peña-Hernández Mario A MA Tabachnikova Alexandra A Homer Robert J RJ Tabacof Laura L Tosto-Mancuso Jenna J Breyman Erica E Kontorovich Amy A McCarthy Dayna D Quezado Martha M Vogel Hannes H Hefti Marco M MM Perl Daniel P DP Liddelow Shane S Folkerth Rebecca R Putrino David D Nath Avindra A Iwasaki Akiko A Monje Michelle M

Cell 20220613 14

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 oligodendr ...[more]

PMID: 35768006

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Project description:Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Dataset Information

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

Publications

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

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