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

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.

SUBMITTER: Song E

PROVIDER: S-EPMC8091032 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Song Eric E Bartley Christopher M CM Chow Ryan D RD Ngo Thomas T TT Jiang Ruoyi R Zamecnik Colin R CR Dandekar Ravi R Loudermilk Rita P RP Dai Yile Y Liu Feimei F Sunshine Sara S Liu Jamin J Wu Wesley W Hawes Isobel A IA Alvarenga Bonny D BD Huynh Trung T McAlpine Lindsay L Rahman Nur-Taz NT Geng Bertie B Chiarella Jennifer J Goldman-Israelow Benjamin B Vogels Chantal B F CBF Grubaugh Nathan D ND Casanovas-Massana Arnau A Phinney Brett S BS Salemi Michelle M Alexander Jessa R JR Gallego Juan A JA Lencz Todd T Walsh Hannah H Wapniarski Anne E AE Mohanty Subhasis S Lucas Carolina C Klein Jon J Mao Tianyang T Oh Jieun J Ring Aaron A Spudich Serena S Ko Albert I AI Kleinstein Steven H SH Pak John J DeRisi Joseph L JL Iwasaki Akiko A Pleasure Samuel J SJ Wilson Michael R MR Farhadian Shelli F SF

Cell reports. Medicine 20210503 5

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-C ...[more]

PMID: 33969321

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Project description:The immune mechanisms of long coronavirus disease 2019 (COVID) are not yet fully understood. We aimed to investigate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific memory immune responses in discharged COVID-19 patients with and without long COVID symptoms. In this cross-sectional study, we included 1041 hospitalized COVID-19 patients with the original virus strain in Wuhan (China) 12 months after initial infection. We simultaneously conducted a questionnaire survey and collected peripheral blood samples from the participants. Based on the presence or absence of long COVID symptoms during the follow-up period, we divided the patients into 2 groups: a long COVID group comprising 480 individuals and a convalescent group comprising 561 individuals. Both groups underwent virus-specific immunological analyses, including enzyme-linked immunosorbent assay, interferon-γ-enzyme-linked immune absorbent spot, and intracellular cytokine staining. At 12 months after infection, 98.5% (1026/1041) of the patients were found to be seropositive and 93.3% (70/75) had detectable SARS-CoV-2-specific memory T cells. The long COVID group had significantly higher levels of receptor binding domain (RBD)-immunoglobulin G (IgG) levels, presented as OD450 values, than the convalescent controls (0.40 ± 0.22 vs 0.37 ± 0.20; P = .022). The magnitude of SARS-CoV-2-specific T-cell responses did not differ significantly between groups, nor did the secretion function of the memory T cells. We did not observe a significant correlation between SARS-CoV-2-IgG and magnitude of memory T cells. This study revealed that long COVID patients had significantly higher levels of RBD-IgG antibodies when compared with convalescent controls. Nevertheless, we did not observe coordinated SARS-CoV-2-specific cellular immunity. As there may be multiple potential causes of long COVID, it is imperative to avoid adopting a "one-size-fits-all" approach to future treatment modalities.

Dataset Information

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

Publications

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

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