» Articles » PMID: 33758854

SARS-CoV-2 Spike Protein Induces Inflammation Via TLR2-dependent Activation of the NF-κB Pathway

Overview
Journal bioRxiv
Date 2021 Mar 24
PMID 33758854
Authors
Affiliations
Soon will be listed here.
Abstract

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1ß, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1 ß in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

References
1.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-422. PMC: 7164771. DOI: 10.1016/S2213-2600(20)30076-X. View

2.
Li Y, Li H, Li M, Zhang L, Xie M . The prevalence, risk factors and outcome of cardiac dysfunction in hospitalized patients with COVID-19. Intensive Care Med. 2020; 46(11):2096-2098. PMC: 7411264. DOI: 10.1007/s00134-020-06205-0. View

3.
Cheung C, Poon L, Ng I, Luk W, Sia S, Wu M . Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol. 2005; 79(12):7819-26. PMC: 1143636. DOI: 10.1128/JVI.79.12.7819-7826.2005. View

4.
Dosch S, Mahajan S, Collins A . SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res. 2009; 142(1-2):19-27. PMC: 2699111. DOI: 10.1016/j.virusres.2009.01.005. View

5.
Vabret N, Britton G, Gruber C, Hegde S, Kim J, Kuksin M . Immunology of COVID-19: Current State of the Science. Immunity. 2020; 52(6):910-941. PMC: 7200337. DOI: 10.1016/j.immuni.2020.05.002. View