SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice
Fabrícia Lima Fontes-Dantas, Gabriel Gripp Fernandes, Elisa Gouvea Gutman, Emanuelle V. de Lima, Leticia S. Antonio, Mariana Beiral Hämmerle, Hannah P. Mota-Araujo, Lilian C. Colodeti, Suzana Maria Bernardino Araújo, Gabrielle M. Froz, Talita Nascimento da Silva, Larissa Araújo Duarte, Andreza Lemos Salvio, Karina Lebeis Pires, Luciane Almeida Amado Leon, Cláudia Cristina Ferreira Vasconcelos, Luciana Romão, Luiz Eduardo Baggio Savio, Jerson L. Silva, Robson da Costa, Julia R. Clarke, Andrea T. Da Poian, Soniza Vieira Alves‐Leon, Giselle F. Passos, Cláudia P. Figueiredo
Abstract
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.