SARS-CoV2 spike protein induces inflammatory molecules through TLR2 in macrophages and monocytes

Abstract

Abstract COVID-19 pandemic caused by SARS-CoV2 infection has emerged as a major public health problem. Excessive inflammation or cytokine storm is considered a major cause of respiratory failure, organ damage, and death of COVID-19 patients. However, the precise mechanism of inflammatory response induced by SARS-CoV2 is poorly understood. We investigated whether the structural proteins of SARS-CoV2 including spike (S), membrane (M), envelope (E), and neucleocapsid (N) are involved in inducing inflammation. Human monocytic cells THP-1 derived macrophages or human peripheral blood mononuclear cells were stimulated with the recombinant structural proteins and measured for the induction of inflammatory cytokines and chemokines. We observed that S protein potently induces IL-6, IL-1b, TNFa, CXCL1, and CCL2 in macrophages and monocytes, while other structural proteins were non-stimulatory. Notably, human lung epithelial cells A549 and human embryonic kidney epithelial cell HEK293T, which express S protein receptor ACE2, did not express cytokines and chemokines in response to S and other structural proteins. We dissected signaling pathways involved in inducing inflammatory molecules in response to S protein. S protein activates the NF-kB pathway in a MyD88 dependent manner. Further, S protein-mediated activation of NF-kB and induction of inflammatory responses were completely abrogated in TLR2-deficient macrophages, suggesting that TLR2 is an innate immune receptor for SARS-CoV2 S protein. Together these data reveal a mechanism of cytokine storm during SARS-CoV2 infection, and points to TLR2 as a potential therapeutic target for COVID-19.