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Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalçın, Kathryn R. Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeff R. Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, View ORCID ProfileJulio Silva, Mario A. Peña-Hernández, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, View ORCID ProfileAvi Nath, View ORCID ProfileAkiko Iwasaki, View ORCID ProfileMichelle Monje
doi: https://doi.org/10.1101/2022.01.07.475453
Anthony Fernández-Castañeda
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Peiwen Lu
2Department of Immunobiology, Yale University, New Haven CT USA
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Anna C. Geraghty
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Eric Song
2Department of Immunobiology, Yale University, New Haven CT USA
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Myoung-Hwa Lee
3National Institute of Neurological Disorders and Stroke, Besthesda MD USA
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Jamie Wood
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Belgin Yalçın
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Kathryn R. Taylor
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Selena Dutton
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Lehi Acosta-Alvarez
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Lijun Ni
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Daniel Contreras-Esquivel
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
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Jeff R. Gehlhausen
2Department of Immunobiology, Yale University, New Haven CT USA
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Jon Klein
2Department of Immunobiology, Yale University, New Haven CT USA
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Carolina Lucas
2Department of Immunobiology, Yale University, New Haven CT USA
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Tianyang Mao
2Department of Immunobiology, Yale University, New Haven CT USA
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Julio Silva
2Department of Immunobiology, Yale University, New Haven CT USA
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Mario A. Peña-Hernández
2Department of Immunobiology, Yale University, New Haven CT USA
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Alexandra Tabachnikova
2Department of Immunobiology, Yale University, New Haven CT USA
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Takehiro Takahashi
2Department of Immunobiology, Yale University, New Haven CT USA
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Laura Tabacof
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Jenna Tosto-Mancuso
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Erica Breyman
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Amy Kontorovich
5Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, NY USA
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Dayna McCarthy
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Martha Quezado
6National Cancer Institute, Besthesda MD USA
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Marco Hefti
7Department of Pathology, University of Iowa, Iowa City, IA USA
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Daniel Perl
8Department of Pathology, Uniformed Services University of Health Sciences, Bethesda MD USA
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Rebecca Folkerth
9Office of Chief Medical Examiner, New York, NY USA
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David Putrino
4Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
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Avi Nath
3National Institute of Neurological Disorders and Stroke, Besthesda MD USA
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Akiko Iwasaki
2Department of Immunobiology, Yale University, New Haven CT USA
10Howard Hughes Medical Institute, Yale University, New Haven CT USA
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  • For correspondence: mmonje@stanford.edu akiko.iwasaki@yale.edu
Michelle Monje
1Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
11Howard Hughes Medical Institute, Stanford University, Stanford CA USA
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  • For correspondence: mmonje@stanford.edu akiko.iwasaki@yale.edu
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Abstract

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.

Competing Interest Statement

A.I. served as a consultant for Spring Discovery, Boehringer Ingelheim and Adaptive Biotechnologies. I.Y. reports being a member of the mRNA-1273 Study Group and has received funding to her institution to conduct clinical research from BioFire, MedImmune, Regeneron, PaxVax, Pfizer, GlaxoSmithKline, Merck, Novavax, Sanofi-Pasteur and Micron. M.M. serves in the scientific advisory board of Cygnal Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 10, 2022.
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Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain
Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalçın, Kathryn R. Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeff R. Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario A. Peña-Hernández, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avi Nath, Akiko Iwasaki, Michelle Monje
bioRxiv 2022.01.07.475453; doi: https://doi.org/10.1101/2022.01.07.475453
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Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain
Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalçın, Kathryn R. Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeff R. Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario A. Peña-Hernández, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avi Nath, Akiko Iwasaki, Michelle Monje
bioRxiv 2022.01.07.475453; doi: https://doi.org/10.1101/2022.01.07.475453

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