SARS-CoV-2 spike protein induces TLR-4-mediated long-term cognitive dysfunction recapitulating post-COVID syndrome

Abstract

COVID-19 pandemic affected the global population in an unprecedented scale, with long-term consequences of SARS CoV-2 infection now emerging as a serious concern. Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. Here we demonstrated that brain exposure to SARS-CoV-2 spike (S) protein through its infusion into the lateral ventricle of adult mice induced late cognitive impairment, hippocampal synapse loss, and microglial engulfment of presynaptic terminals. Additionally, TLR4 blockage prevented Sassociated detrimental effects on memory in mice and TLR4 single nucleotide polymorphism (SNP) rs10759931 was associated with late cognitive outcome in mild COVID-19-recovered patients. Collectively, these findings indicate that S protein directly impacts the brain and identify TLR4 as a key target to prevent cognitive dysfunction. To our knowledge, this is the first animal model that recapitulates postCOVID cognitive impairment, opening new avenues for developing new strategies to prevent or treat the neurological outcomes of COVID-19.

A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

“…The detection of SARS-CoV-2 antigen, perhaps of intestinal origin (27), in the bloodstream of MIS-C patients supports this scenario, particularly since the SARS-CoV-2 Spike glycoprotein can act as TLR ligand (50)(51)(52)(53)(54). Moreover, the activation of negative feedback responses induced by high levels of proinflammatory mediators in the bloodstream likely concurs to render innate immune cells of children with MIS-C unable to respond to further challenge.…”

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

“…Binding to these receptors induces premature cellular senescence in many cell types, including ECs and the result is disruption of endothelial barrier [247][248][249][250][251]. In the GI tract, dysfunctional HMGB1 signaling with RAGE and TLR4, promotes IBD, chronic pain, and the illnesses FM, ME/CFS, long COVID, and GWI (in animal models of this disease) [252][253][254][255][256][257][258].…”