Cell Reports (Mar 2023)
SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice
- 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
Affiliations
- Fabricia L. Fontes-Dantas
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
- Gabriel G. Fernandes
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Elisa G. Gutman
- Translational Neuroscience Laboratory (LabNet), Post-Graduate Program in Neurology, Federal University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil; Clinical Medicine Post-graduation Program, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Emanuelle V. De Lima
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Leticia S. Antonio
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Mariana B. Hammerle
- Clinical Medicine Post-graduation Program, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Hannah P. Mota-Araujo
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Lilian C. Colodeti
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Suzana M.B. Araújo
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Gabrielle M. Froz
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Talita N. da Silva
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Larissa A. Duarte
- Translational Neuroscience Laboratory (LabNet), Post-Graduate Program in Neurology, Federal University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil; Clinical Medicine Post-graduation Program, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Andreza L. Salvio
- Translational Neuroscience Laboratory (LabNet), Post-Graduate Program in Neurology, Federal University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil
- Karina L. Pires
- Neurology Department, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil
- Luciane A.A. Leon
- Laboratório de Desenvolvimento Tecnológico em Virologia, IOC/FIOCRUZ, Rio de Janeiro, RJ, Brazil
- Claudia Cristina F. Vasconcelos
- Neurology Department, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil
- Luciana Romão
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Luiz Eduardo B. Savio
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Jerson L. Silva
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Robson da Costa
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Julia R. Clarke
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Andrea T. Da Poian
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Corresponding author
- Soniza V. Alves-Leon
- Translational Neuroscience Laboratory (LabNet), Post-Graduate Program in Neurology, Federal University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil; Division of Neurology, Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Corresponding author
- Giselle F. Passos
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Corresponding author
- Claudia P. Figueiredo
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 3
p. 112189
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.
