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

Eric Song(Yale University), Christopher M. Bartley(Howard Hughes Medical Institute), Ryan D. Chow(Yale University), Thomas Ngo(University of California, San Francisco), Ruoyi Jiang(Yale University), Colin R. Zamecnik(University of California, San Francisco), Ravi Dandekar(University of California, San Francisco), Rita P. Loudermilk(University of California, San Francisco), Yile Dai(Yale University), Feimei Liu(Yale University), Sara Sunshine(University of California, San Francisco), Jamin Liu(University of California, San Francisco), Wesley Wu(Chan Zuckerberg Initiative (United States)), Isobel A. Hawes(University of California, San Francisco), Bonny D. Alvarenga(University of California, San Francisco), Trung Huynh(University of California, San Francisco), Lindsay McAlpine(Yale University), Nur-Taz Rahman(Yale University), Bertie Geng(Yale University), Jennifer Chiarella(Yale University), Benjamin Israelow(Whitney Museum of American Art), Chantal B. F. Vogels(Yale University), Nathan D. Grubaugh(Yale University), Arnau Casanovas‐Massana(Yale University), Brett S. Phinney(University of California, Davis), Michelle Salemi(University of California, Davis), Jessa Alexander(University of California, San Francisco), Juan A. Gallego(Feinstein Institute for Medical Research), Todd Lencz(Feinstein Institute for Medical Research), Hannah Walsh(Yale University), Anne E. Wapniarski(University of California, San Francisco), Subhasis Mohanty(Yale University), Carolina Lucas(Yale University), Jon Klein(Yale University), Tianyang Mao(Yale University), Jieun Oh(Yale University), Aaron M. Ring(Yale University), Serena Spudich(Yale University), Albert I. Ko(Yale University), Steven H. Kleinstein(Yale University), John E. Pak(Chan Zuckerberg Initiative (United States)), Joseph L. DeRisi(University of California, San Francisco), Akiko Iwasaki(Howard Hughes Medical Institute), Samuel J. Pleasure(University of California, San Francisco), Michael R. Wilson(University of California, San Francisco), Shelli Farhadian(Yale University)
Cell Reports Medicine
May 1, 2021
10.1016/j.xcrm.2021.100288
Cited by 190Open Access
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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.

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