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Keywords COVID-19; long COVID; cognitive impairment; neuroinflammation; microglia; hippocampal neurogenesis; oligodendrocytes; myelin; H1N1 influenza Highlights * Respiratory COVID induces CSF cytokine elevation and microglial reactivity * CCL11 activates hippocampal microglia and impairs neurogenesis * Respiratory COVID causes persistent loss of oligodendrocytes and myelinated axons * Respiratory influenza causes similar but less persistent cellular dysregulation Summary 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. Author Affiliation: (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) Departments of Neuroscience & Physiology and of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA (13) Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA (14) Office of Chief Medical Examiner, New York, NY, USA (15) Howard Hughes Medical Institute, Yale University, New Haven, CT, USA (16) Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA * Corresponding author Article History: Received 7 January 2022; Revised 4 May 2022; Accepted 7 June 2022 (miscellaneous) Published: June 13, 2022 (footnote)17 These authors contributed equally (footnote)18 These authors contributed equally (footnote)19 Lead contact Byline: Anthony Fernández-Castañeda (1,17), Peiwen Lu (2,17), Anna C. Geraghty (1,17), Eric Song (2,17), Myoung-Hwa Lee (3), Jamie Wood (4), Michael R. O'Dea (5), Selena Dutton (1), Kiarash Shamardani (1), Kamsi Nwangwu (1), Rebecca Mancusi (1), Belgin Yalçin (1), Kathryn R. Taylor (1), Lehi Acosta-Alvarez (1), Karen Malacon (1), Michael B. Keough (1), Lijun Ni (1), Pamelyn J. Woo (1), Daniel Contreras-Esquivel (1), Angus Martin Shaw Toland (6), Jeff R. Gehlhausen (2), Jon Klein (2), Takehiro Takahashi (2), Julio Silva (2), Benjamin Israelow (2), Carolina Lucas (2), Tianyang Mao (2), Mario A. Peña-Hernández (2), Alexandra Tabachnikova (2), Robert J. Homer (7), Laura Tabacof (4), Jenna Tosto-Mancuso (4), Erica Breyman (4), Amy Kontorovich (8), Dayna McCarthy (4), Martha Quezado (9), Hannes Vogel (6), Marco M. Hefti (10), Daniel P. Perl (11), Shane Liddelow (5,12,13), Rebecca Folkerth (14), David Putrino (4), Avindra Nath (3), Akiko Iwasaki [akiko.iwasaki@yale.edu] (2,15,18,*), Michelle Monje [mmonje@stanford.edu] (1,6,16,18,19,**)