Differential effects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions

Journal of Neuroinflammation

Research

Christophe J. Queval¹  Alizé Proust²  Robert J. Wilkinson³  Lorin Adams⁴  Michael Bennett⁴  Ruth Harvey⁴ 

[1] High Throughput Screening Laboratory, The Francis Crick Institute, NW1 1AT, London, UK;Tuberculosis Laboratory, The Francis Crick Institute, NW1 1AT, London, UK;Tuberculosis Laboratory, The Francis Crick Institute, NW1 1AT, London, UK;Department of Infectious Diseases, Imperial College London, W12 0NN, London, UK;Institute of Infectious Disease and Molecular Medicine and Department of Medicine, Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Observatory, 7925, Cape Town, Republic of South Africa;Worldwide Influenza Centre, The Francis Crick Institute, NW1 1AT, London, UK;

关键词: SARS-CoV-2;    Blood–brain barrier;    Central nervous system;    Brain;    Excitotoxicity;    Astrocytes;    Brain microvascular endothelial cells;    Microglia;    Pericytes;   

DOI  :  10.1186/s12974-023-02861-3

 received in 2023-03-30, accepted in 2023-07-25,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAlthough mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear.MethodsWe used primary human pericytes, foetal astrocytes, endothelial cells and a microglial cell line to investigate the effect of several SARS-CoV-2 variants of concern or interest on their functional activities. Cells and a 3D blood–brain barrier model were infected with the wild-type form of SARS-CoV-2, Alpha, Beta, Delta, Eta, or Omicron (BA.1) variants at various MOI. Cells and supernatant were used to evaluate cell susceptibility to the virus using a microscopic assay as well as effects of infection on (i) cell metabolic activity using a colorimetric MTS assay; (ii) viral cytopathogenicity using the xCELLigence system; (iii) extracellular glutamate concentration by fluorometric assay; and (iv) modulation of blood–brain barrier permeability.ResultsWe demonstrate that productive infection of brain cells is SARS-CoV-2 variant dependent and that all the variants induce stress to CNS cells. The wild-type virus was cytopathic to all cell types except astrocytes, whilst Alpha and Beta variants were only cytopathic for pericytes, and the Omicron variant cytopathic for endothelial cells and pericytes. Lastly wild-type virus increases blood–brain barrier permeability and all variants, except Beta, modulate extracellular glutamate concentration, which can lead to excitotoxicity or altered neurotransmission.ConclusionsThese results suggest that SARS-CoV-2 is neurotropic, with deleterious consequences for the blood–brain barrier integrity and central nervous system cells, which could underlie neurological disorders following SARS-CoV-2 infection.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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