Recombinant SARS-CoV-2 Spike Protein and its Receptor Binding Domain stimulate release of different pro-inflammatory mediators via activation of distinct receptors on human microglia cells (preprint)

ABSTRACT

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor Angiotensin Converting Enzyme 2 (ACE2) on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that SARS-CoV-2 infection produces neuroinflammation associated with neurological, neuropsychiatric, and cognitive symptoms persists well past the resolution of the infection, known as post-COVID-19 sequalae or Long-COVID. The neuroimmune mechanism(s) involved in Long-COVID have not been adequately characterized. In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6 and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18 and S100B via ACE2 signaling. These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with Long-COVID.