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SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

Authors :
Fabricia L. Fontes-Dantas
Gabriel G. Fernandes
Elisa G. Gutman
Emanuelle V. De Lima
Leticia S. Antonio
Mariana B. Hammerle
Hannah P. Mota-Araujo
Lilian C. Colodeti
Suzana M.B. Araújo
Gabrielle M. Froz
Talita N. da Silva
Larissa A. Duarte
Andreza L. Salvio
Karina L. Pires
Luciane A.A. Leon
Claudia Cristina F. Vasconcelos
Luciana Romão
Luiz Eduardo B. Savio
Jerson L. Silva
Robson da Costa
Julia R. Clarke
Andrea T. Da Poian
Soniza V. Alves-Leon
Giselle F. Passos
Claudia P. Figueiredo
Source :
Cell Reports, Vol 42, Iss 3, Pp 112189- (2023)
Publication Year :
2023
Publisher :
Elsevier, 2023.

Abstract

Summary: Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

Details

Language :
English
ISSN :
22111247
Volume :
42
Issue :
3
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.fe134363e486421c960c5fd3b4c479bc
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2023.112189