SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

eLife

John W Schoggins¹  Shahanshah Khan²  Hasan Zaki²  Mahnoush S Shafiei²  Christopher Longoria³  Rashmin C Savani³ 

[1] Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, United States;Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States;Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, United States;

关键词: SARS-CoV-2;    COVID-19;    spike protein;    cytokine storm;    TLR2;    inflammation;   

DOI  :  10.7554/eLife.68563

来源: DOAJ

【 摘 要 】

The 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 induced inflammatory cytokines and chemokines, including IL-6, IL-1β, TNFα, 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 nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited 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 was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein-induced IL-6, TNF-α, and IL-1β in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-κB pathway. Taken 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.

【 授权许可】

Unknown