Cell Reports Medicine (May 2021)
Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms
- Eric Song,
- Christopher M. Bartley,
- Ryan D. Chow,
- Thomas T. Ngo,
- Ruoyi Jiang,
- Colin R. Zamecnik,
- Ravi Dandekar,
- Rita P. Loudermilk,
- Yile Dai,
- Feimei Liu,
- Sara Sunshine,
- Jamin Liu,
- Wesley Wu,
- Isobel A. Hawes,
- Bonny D. Alvarenga,
- Trung Huynh,
- Lindsay McAlpine,
- Nur-Taz Rahman,
- Bertie Geng,
- Jennifer Chiarella,
- Benjamin Goldman-Israelow,
- Chantal B.F. Vogels,
- Nathan D. Grubaugh,
- Arnau Casanovas-Massana,
- Brett S. Phinney,
- Michelle Salemi,
- Jessa R. Alexander,
- Juan A. Gallego,
- Todd Lencz,
- Hannah Walsh,
- Anne E. Wapniarski,
- Subhasis Mohanty,
- Carolina Lucas,
- Jon Klein,
- Tianyang Mao,
- Jieun Oh,
- Aaron Ring,
- Serena Spudich,
- Albert I. Ko,
- Steven H. Kleinstein,
- John Pak,
- Joseph L. DeRisi,
- Akiko Iwasaki,
- Samuel J. Pleasure,
- Michael R. Wilson,
- Shelli F. Farhadian
Affiliations
- Eric Song
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Corresponding author
- Christopher M. Bartley
- Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
- Ryan D. Chow
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Thomas T. Ngo
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
- Ruoyi Jiang
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Colin R. Zamecnik
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Ravi Dandekar
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Rita P. Loudermilk
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Yile Dai
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Feimei Liu
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Sara Sunshine
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
- Jamin Liu
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA; University of California, Berkeley—University of California, San Francisco Gradate Program in Bioengineering, Berkeley, CA, USA
- Wesley Wu
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Isobel A. Hawes
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
- Bonny D. Alvarenga
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Trung Huynh
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Lindsay McAlpine
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Nur-Taz Rahman
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Bertie Geng
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
- Jennifer Chiarella
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Benjamin Goldman-Israelow
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT, USA
- Chantal B.F. Vogels
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
- Nathan D. Grubaugh
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
- Arnau Casanovas-Massana
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
- Brett S. Phinney
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA
- Michelle Salemi
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA
- Jessa R. Alexander
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Juan A. Gallego
- Institute for Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA; Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Todd Lencz
- Institute for Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA; Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Hannah Walsh
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
- Anne E. Wapniarski
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Subhasis Mohanty
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
- Carolina Lucas
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Jon Klein
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Tianyang Mao
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Jieun Oh
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Aaron Ring
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Serena Spudich
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Albert I. Ko
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
- Steven H. Kleinstein
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
- John Pak
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Joseph L. DeRisi
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA
- Akiko Iwasaki
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
- Samuel J. Pleasure
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
- Michael R. Wilson
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
- Shelli F. Farhadian
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA; Corresponding author
- Journal volume & issue
-
Vol. 2,
no. 5
p. 100288
Abstract
Summary: Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.
