TY - JOUR
T1 - Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
AU - Fernández-Castañeda, Anthony
AU - Lu, Peiwen
AU - Geraghty, Anna C.
AU - Song, Eric
AU - Lee, Myoung Hwa
AU - Wood, Jamie
AU - O'Dea, Michael R.
AU - Dutton, Selena
AU - Shamardani, Kiarash
AU - Nwangwu, Kamsi
AU - Mancusi, Rebecca
AU - Yalçın, Belgin
AU - Taylor, Kathryn R.
AU - Acosta-Alvarez, Lehi
AU - Malacon, Karen
AU - Keough, Michael B.
AU - Ni, Lijun
AU - Woo, Pamelyn J.
AU - Contreras-Esquivel, Daniel
AU - Toland, Angus Martin Shaw
AU - Gehlhausen, Jeff R.
AU - Klein, Jon
AU - Takahashi, Takehiro
AU - Silva, Julio
AU - Israelow, Benjamin
AU - Lucas, Carolina
AU - Mao, Tianyang
AU - Peña-Hernández, Mario A.
AU - Tabachnikova, Alexandra
AU - Homer, Robert J.
AU - Tabacof, Laura
AU - Tosto-Mancuso, Jenna
AU - Breyman, Erica
AU - Kontorovich, Amy
AU - McCarthy, Dayna
AU - Quezado, Martha
AU - Vogel, Hannes
AU - Hefti, Marco M.
AU - Perl, Daniel P.
AU - Liddelow, Shane
AU - Folkerth, Rebecca
AU - Putrino, David
AU - Nath, Avindra
AU - Iwasaki, Akiko
AU - Monje, Michelle
N1 - Funding Information:
The authors would like to thank members of the Yale Center for Genomic Analysis (YCGA), especially Guilin Wang and Jack Wheeler for help with 10X sequencing, the Human Immune Monitoring Core at Stanford, Erin Gibson for input on the manuscript, and Yoon Seok Kim for help with figure formatting. The graphical abstract was created with BioRender.com. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS092597 to M.M. NS003130 and NS003157 to A.N. K23NS109284 to M.M.H.), NIH Director's pioneer award (DP1NS111132 to M.M. supplement DP1NS111132-S1 to A.F.-C.), NIH National Eye Institute (R01EY033353 to S.A.L.), National Institute of Allergy and Infectious Diseases (R01AI157488 to A.I.), FDA Office of Women's Health Research Centers of Excellence in Regulatory Science and Innovation (CERSI) (to A.I.), Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to M.M.), Cancer Research UK (to M.M.), Waxman Family Research Fund (to M.M. and A.C.G.), Fast Grant from Emergent Ventures at the Mercatus Center (to A.I.), RTW Foundation (D.P.) MD Anderson Neurodegenerative Disease Consortium (to S.A.L.), the Cure Alzheimer's Fund (to S.A.L.), the Howard Hughes Medical Institute Collaborative COVID-19 Initiative (to A.I.), and the Howard Hughes Medical Institute (to A.I. and M.M.). Conceptualization, methodology, validation, and visualization were performed by M.M. A.I. A.F.-C. P.L. A.C.G. and E.S.; formal analysis by A.F.-C. A.C.G. M.R.O. K.S. R.M. M.B.K. S.L. R.F. M.M.H. H.V. and M.M.; resources provided by M.M. and A.I.; investigation was performed by A.F.-C. P.L. A.C.G. E.S. M.-H.L. J.W. S.D. K.N. B.Y. K.R.T. L.A.-A. K.M. L.N. P.J.W. D.C.-E. A.M.S.T. J.R.G. J.K. T.T. J.S. B.I. C.L. T.M. M.A.P.-H. A.T. R.J.H. L.T. J.T.-M. E.B. A.K. D.M.C. M.Q. H.V. M.M.H. D.P.P. R.F. D.P. and A.N.; writing – original draft by M.M.; writing – review & editing by A.F.-C. P.L. A.C.G. E.S. S.L. A.I. and M.M.; data curation by E.S. M.R.O. S.L.; supervised by M.M. A.I. H.V. S.L. D.P. and A.N.; funding acquisition by M.M. A.I. and D.P. A.I. served as a consultant for Spring Discovery, Boehringer Ingelheim (Ingelheim, Germany), and Adaptive Biotechnologies. M.M. serves in the scientific advisory board of Cygnal Therapeutics. S.A.L. sits on the scientific advisory board and has a financial interest in AstronauTx Ltd. The opinions and assertions expressed herein are those of the authors and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. We actively worked to promote gender balance in our reference list.
Funding Information:
The authors would like to thank members of the Yale Center for Genomic Analysis (YCGA), especially Guilin Wang and Jack Wheeler for help with 10X sequencing, the Human Immune Monitoring Core at Stanford, Erin Gibson for input on the manuscript, and Yoon Seok Kim for help with figure formatting. The graphical abstract was created with BioRender.com. This work was supported by grants from the National Institute of Neurological Disorders and Stroke ( R01NS092597 to M.M., NS003130 and NS003157 to A.N., K23NS109284 to M.M.H.), NIH Director’s pioneer award ( DP1NS111132 to M.M., supplement DP1NS111132-S1 to A.F.-C.), NIH National Eye Institute ( R01EY033353 to S.A.L.), National Institute of Allergy and Infectious Diseases ( R01AI157488 to A.I.), FDA Office of Women’s Health Research Centers of Excellence in Regulatory Science and Innovation (CERSI) (to A.I.), Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to M.M.), Cancer Research UK (to M.M.), Waxman Family Research Fund (to M.M. and A.C.G.), Fast Grant from Emergent Ventures at the Mercatus Center (to A.I.), RTW Foundation (D.P.) MD Anderson Neurodegenerative Disease Consortium (to S.A.L.), the Cure Alzheimer’s Fund (to S.A.L.), the Howard Hughes Medical Institute Collaborative COVID-19 Initiative (to A.I.), and the Howard Hughes Medical Institute (to A.I. and M.M.).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/7/7
Y1 - 2022/7/7
N2 - 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.
AB - 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.
KW - COVID-19
KW - H1N1 influenza
KW - cognitive impairment
KW - hippocampal neurogenesis
KW - long COVID
KW - microglia
KW - myelin
KW - neuroinflammation
KW - oligodendrocytes
UR - http://www.scopus.com/inward/record.url?scp=85133162766&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.06.008
DO - 10.1016/j.cell.2022.06.008
M3 - Article
C2 - 35768006
AN - SCOPUS:85133162766
VL - 185
SP - 2452-2468.e16
JO - Cell
JF - Cell
SN - 0092-8674
IS - 14
ER -