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

doi:10.1016/j.xcrm.2021.100288

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

Cell Rep Med. 2021 May 18;2(5):100288. doi: 10.1016/j.xcrm.2021.100288. Epub 2021 May 3.

Authors

Eric Song¹, Christopher M Bartley^{2

3

4}, Ryan D Chow⁵, Thomas T Ngo^{3

4}, Ruoyi Jiang¹, Colin R Zamecnik^{3

6}, Ravi Dandekar^{3

6}, Rita P Loudermilk^{3

6}, Yile Dai¹, Feimei Liu¹, Sara Sunshine⁷, Jamin Liu^{7

8}, Wesley Wu⁹, Isobel A Hawes^{3

6

10}, Bonny D Alvarenga^{3

6}, Trung Huynh^{3

6}, Lindsay McAlpine¹¹, Nur-Taz Rahman¹¹, Bertie Geng¹², Jennifer Chiarella¹¹, Benjamin Goldman-Israelow^{1

13}, Chantal B F Vogels¹⁴, Nathan D Grubaugh¹⁴, Arnau Casanovas-Massana¹⁴, Brett S Phinney¹⁵, Michelle Salemi¹⁵, Jessa R Alexander^{3

6}, Juan A Gallego^{16

17

18}, Todd Lencz^{16

17

18}, Hannah Walsh¹², Anne E Wapniarski^{3

6}, Subhasis Mohanty¹², Carolina Lucas¹, Jon Klein¹, Tianyang Mao¹, Jieun Oh¹, Aaron Ring¹, Serena Spudich¹¹, Albert I Ko^{12

14}, Steven H Kleinstein^{1

19

20}, John Pak⁹, Joseph L DeRisi^{7

9}, Akiko Iwasaki^{1

21

22}, Samuel J Pleasure^{3

6}, Michael R Wilson^{3

6}, Shelli F Farhadian^{11

12}

Affiliations

¹ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
² Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA.
³ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁸ University of California, Berkeley-University of California, San Francisco Gradate Program in Bioengineering, Berkeley, CA, USA.
⁹ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁰ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
¹² Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA.
¹³ Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT, USA.
¹⁴ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
¹⁵ Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA.
¹⁶ Institute for Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
¹⁷ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
¹⁸ Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
¹⁹ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
²⁰ Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
²¹ Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT, USA.
²² Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; autoimmunity; cerebrospinal fluid; neurological infection.

Abstract

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