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

Anthony Fernández-Castañeda; Peiwen Lu; Anna C Geraghty; Eric Song; Myoung-Hwa Lee; Jamie Wood; Michael R O'Dea; Selena Dutton; Kiarash Shamardani; Kamsi Nwangwu; Rebecca Mancusi; Belgin Yalçın; Kathryn R Taylor; Lehi Acosta-Alvarez; Karen Malacon; Michael B Keough; Lijun Ni; Pamelyn J Woo; Daniel Contreras-Esquivel; Angus Martin Shaw Toland; Jeff R Gehlhausen; Jon Klein; Takehiro Takahashi; Julio Silva; Benjamin Israelow; Carolina Lucas; Tianyang Mao; Mario A Peña-Hernández; Alexandra Tabachnikova; Robert J Homer; Laura Tabacof; Jenna Tosto-Mancuso; Erica Breyman; Amy Kontorovich; Dayna McCarthy; Martha Quezado; Hannes Vogel; Marco M Hefti; Daniel P Perl; Shane Liddelow; Rebecca Folkerth; David Putrino; Avindra Nath; Akiko Iwasaki; Michelle Monje

doi:10.1016/j.cell.2022.06.008

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

Cell. 2022 Jul 7;185(14):2452-2468.e16. doi: 10.1016/j.cell.2022.06.008. Epub 2022 Jun 13.

Authors

Anthony Fernández-Castañeda¹, Peiwen Lu², Anna C Geraghty¹, Eric Song², Myoung-Hwa Lee³, Jamie Wood⁴, Michael R O'Dea⁵, Selena Dutton¹, Kiarash Shamardani¹, Kamsi Nwangwu¹, Rebecca Mancusi¹, Belgin Yalçın¹, Kathryn R Taylor¹, Lehi Acosta-Alvarez¹, Karen Malacon¹, Michael B Keough¹, Lijun Ni¹, Pamelyn J Woo¹, Daniel Contreras-Esquivel¹, Angus Martin Shaw Toland⁶, Jeff R Gehlhausen², Jon Klein², Takehiro Takahashi², Julio Silva², Benjamin Israelow², Carolina Lucas², Tianyang Mao², Mario A Peña-Hernández², Alexandra Tabachnikova², Robert J Homer⁷, Laura Tabacof⁴, Jenna Tosto-Mancuso⁴, Erica Breyman⁴, Amy Kontorovich⁸, Dayna McCarthy⁴, Martha Quezado⁹, Hannes Vogel⁶, Marco M Hefti¹⁰, Daniel P Perl¹¹, Shane Liddelow¹², Rebecca Folkerth¹³, David Putrino⁴, Avindra Nath³, Akiko Iwasaki¹⁴, Michelle Monje¹⁵

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
² Department of Immunobiology, Yale University, New Haven, CT, USA.
³ National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁴ Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA.
⁵ Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
⁶ Department of Pathology, Stanford University, Stanford, CA, USA.
⁷ Department of Pathology, Yale University, New Haven, CT, USA.
⁸ Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, NY, USA.
⁹ National Cancer Institute, Bethesda, MD, USA.
¹⁰ Department of Pathology, University of Iowa, Iowa City, IA, USA.
¹¹ Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
¹² Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA; Departments of Neuroscience & Physiology and of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA; Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA.
¹³ Office of Chief Medical Examiner, New York, NY, USA.
¹⁴ Department of Immunobiology, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. Electronic address: akiko.iwasaki@yale.edu.
¹⁵ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. Electronic address: mmonje@stanford.edu.

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.

Keywords: COVID-19; H1N1 influenza; cognitive impairment; hippocampal neurogenesis; long COVID; microglia; myelin; neuroinflammation; oligodendrocytes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
COVID-19*
Humans
Influenza, Human* / pathology
Mice
Microglia / pathology
Myelin Sheath
Neoplasms* / pathology
SARS-CoV-2

Abstract

Publication types

MeSH terms

Grants and funding