Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

Immunity. 2021 Jan 12;54(1):164-175.e6. doi: 10.1016/j.immuni.2020.12.011. Epub 2020 Dec 23.


Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4+ T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.

Keywords: COVID-19; Neuro-COVID; SARS-CoV-2; T cell exhaustion; cerebrospinal fluid; interferon-stimulated genes; neurological manifestation; single-cell RNA sequencing; transcriptomics.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / cerebrospinal fluid
  • COVID-19 / complications
  • COVID-19 / immunology*
  • COVID-19 / pathology
  • Cell Differentiation
  • Cerebrospinal Fluid / immunology
  • Encephalitis, Viral / cerebrospinal fluid
  • Encephalitis, Viral / immunology
  • Gene Expression Profiling
  • Humans
  • Interferons / genetics
  • Interferons / immunology
  • Leukocytes / immunology
  • Lymphocyte Activation
  • Monocytes / immunology*
  • Nervous System Diseases / cerebrospinal fluid
  • Nervous System Diseases / etiology
  • Nervous System Diseases / immunology*
  • Nervous System Diseases / pathology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • SARS-CoV-2 / immunology
  • Single-Cell Analysis
  • T-Lymphocytes / immunology*


  • Receptors, Antigen, T-Cell
  • Interferons