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Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement

View ORCID ProfileEric Song, View ORCID ProfileChristopher M. Bartley, Ryan D. Chow, Thomas T. Ngo, View ORCID ProfileRuoyi Jiang, Colin R. Zamecnik, Ravi Dandekar, Rita P. Loudermilk, Yile Dai, Feimei Liu, 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 Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, Joseph L. DeRisi, View ORCID ProfileAkiko Iwasaki, Samuel J. Pleasure, View ORCID ProfileMichael R. Wilson, Shelli F. Farhadian
doi: https://doi.org/10.1101/2020.09.11.293464
Eric Song
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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  • For correspondence: eric.song@yale.edu Michael.wilson@ucsf.edu shelli.farhadian@yale.edu
Christopher M. Bartley
2Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
4Department of Psychiatry, University of California, San Francisco, CA, USA
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Ryan D. Chow
5Department of Genetics, Yale School of Medicine, New Haven, CT, USA
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Thomas T. Ngo
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
4Department of Psychiatry, University of California, San Francisco, CA, USA
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Ruoyi Jiang
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Colin R. Zamecnik
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Ravi Dandekar
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Rita P. Loudermilk
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Yile Dai
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Feimei Liu
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Isobel A. Hawes
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
7Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA
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Bonny D. Alvarenga
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Trung Huynh
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Lindsay McAlpine
8Department of Neurology, Yale School of Medicine, New Haven, CT, USA
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Nur-Taz Rahman
9Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, Connecticut, USA
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Bertie Geng
10Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
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Jennifer Chiarella
8Department of Neurology, Yale School of Medicine, New Haven, CT, USA
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Benjamin Goldman-Israelow
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
9Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, Connecticut, USA
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Chantal B.F. Vogels
11Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
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Nathan D. Grubaugh
11Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
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Arnau Casanovas-Massana
11Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
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Brett S. Phinney
12Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, CA 95616, USA
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Michelle Salemi
12Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, CA 95616, USA
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Jessa Alexander
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Juan A. Gallego
13Institute for Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA
14Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA
15Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York USA
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Todd Lencz
13Institute for Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA
14Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA
15Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York USA
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Hannah Walsh
9Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, Connecticut, USA
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Carolina Lucas
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Jon Klein
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Tianyang Mao
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Jieun Oh
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Aaron Ring
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Serena Spudich
8Department of Neurology, Yale School of Medicine, New Haven, CT, USA
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Albert I. Ko
10Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
11Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
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Steven H. Kleinstein
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
16Department of Pathology, Yale School of Medicine, New Haven, CT, USA
17Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
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Joseph L. DeRisi
18Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
19Chan Zuckerberg Biohub, San Francisco, CA, USA
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Akiko Iwasaki
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
20Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT, USA
21Howard Hughes Medical Institute, Chevy Chase, MD, USA
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Samuel J. Pleasure
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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Michael R. Wilson
3Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
6Department of Neurology, University of California, San Francisco, CA, USA
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  • For correspondence: eric.song@yale.edu Michael.wilson@ucsf.edu shelli.farhadian@yale.edu
Shelli F. Farhadian
8Department of Neurology, Yale School of Medicine, New Haven, CT, USA
10Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
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  • For correspondence: eric.song@yale.edu Michael.wilson@ucsf.edu shelli.farhadian@yale.edu
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Abstract

One third of COVID-19 patients develop significant neurological symptoms, yet SARS-CoV-2 is rarely detected in central nervous system (CNS) tissue, suggesting a potential role for parainfectious processes, including neuroimmune responses. We therefore examined immune parameters in cerebrospinal fluid (CSF) and blood samples from a cohort of patients with COVID-19 and significant neurological complications. We found divergent immunological responses in the CNS compartment, including increased levels of IL-12 and IL-12-associated innate and adaptive immune cell activation. Moreover, we found increased proportions of B cells in the CSF relative to the periphery and evidence of clonal expansion of CSF B cells, suggesting a divergent intrathecal humoral response to SARS-CoV-2. Indeed, all COVID-19 cases examined had anti-SARS-CoV-2 IgG antibodies in the CSF whose target epitopes diverged from serum antibodies. We directly examined whether CSF resident antibodies target self-antigens and found a significant burden of CNS autoimmunity, with the CSF from most patients recognizing neural self-antigens. Finally, we produced a panel of monoclonal antibodies from patients’ CSF and show that these target both anti-viral and anti-neural antigens—including one mAb specific for the spike protein that also recognizes neural tissue. This exploratory immune survey reveals evidence of a compartmentalized and self-reactive immune response in the CNS meriting a more systematic evaluation of neurologically impaired COVID-19 patients.

One Sentence Summary A subset of COVID-19 patients with neurologic impairment show cerebrospinal fluid-specific immune alterations that point to both neuroinvasion and anti-neural autoimmunity as potential causes of impairment.

Competing Interest Statement

The authors have declared no competing interest.

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-NC-ND 4.0 International license.
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Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement
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, 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 Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, Joseph L. DeRisi, Akiko Iwasaki, Samuel J. Pleasure, Michael R. Wilson, Shelli F. Farhadian
bioRxiv 2020.09.11.293464; doi: https://doi.org/10.1101/2020.09.11.293464
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Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement
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, 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 Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, Joseph L. DeRisi, Akiko Iwasaki, Samuel J. Pleasure, Michael R. Wilson, Shelli F. Farhadian
bioRxiv 2020.09.11.293464; doi: https://doi.org/10.1101/2020.09.11.293464

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