Toll-like receptor 2 (TLR2) forms heterodimers with TLR1 and TLR6 to sense bacterial components such as lipoproteins or lipoteichoic acids. TLR2 has been also reported to respond to viral infections caused by herpes simplex virus (HSV) (Leoni V et al. 2012), measles virus (Bieback K et al. 2002), Dengue virus (Chen J et al. 2015) and SARS-CoV-2 (Zheng M et al. 2021; Khan S et al. 2021; reviewed in Zhou R et al. 2021). The expression of TLR2, TLR4 and the adaptor protein MyD88 were increased in patients with severe and critical COVID-19 (Desterke C et al. 2020; Zheng M et al. 2021). Similar results were observed for expression levels of TLR1, TLR4, TLR5, TLR8 and TLR9 (Zheng M et al. 2021). Further, inhibition of TLR2 signaling by the specific TLR2 inhibitor oxPAPC reduced secretion of TNF-α, IFN-γ, IL-1α, IL-6, CXCL10, MCP-1, G-CSF and CCL3 in SARS-CoV-2-infected human peripheral blood mononuclear (PBMCs) cells (Zheng M et al. 2021). Similarly, in SARS-CoV-2–infected mice, treatment with TLR2 inhibitor decreased amounts of pro-inflammatory cytokines IL-6, CXCL10 and MCP-1 and increased survival of the infected mice (Zheng M et al. 2021). In bronchoalveolar lavage fluids (BALF) of COVID-19 patients, the expression of TLR2 and TLR4 is correlated with disease severity: TLR2 expression increases with disease severity, especially in the CD14-CD16 cell populations, whereas TLR4 induction is less dramatic (Desterke C et al. 2020). Further, intra-nasal administration of the TLR2:TLR6 agonist reduces levels of viral RNA in the nose and throat in a SARS-CoV-2 ferret infection model (Proud PC et al. 2021). These data suggest that SARS-CoV-2 infection is sensed by TLR2 (reviewed in Sariol A & Perlman S 2021). SARS-CoV-2 spike (S) and envelope (E) proteins were reported to activate the TLR2 signaling pathway leading to the production of inflammatory cytokines in human and mouse cells (Zheng M et al. 2021; Khan S et al. 2021). As the components of the S3:M:E:encapsidated SARS coronavirus genomic RNA:7a:O-glycosyl 3a tetramer complex, both S and E are embedded in the virion membrane. Viral E can oligomerize to form pentamers. Viral E co-immunoprecipitated with TLR2 from lysates of human embryonic kidney 293T (HEK293T) cells after incubation of purified E protein from SARS-CoV-2 with overexpressed human TLR2 (Zheng M et al. 2021). This interaction is thought to induces TLR2-driven inflammation in response to SARS-CoV-2 infection (Zheng M et al. 2021). The potential role of TLR2 in the recognition of SARS-CoV-2 S is controversial and needs further studies (Khan S et al. 2021; Shirato K & Kizaki T 2021).

This Reactome event shows binding of TLR2:TLR1 associated with the host cell plasma membrane to SARS-CoV-2 E pentamer which is incorporated into mature virions as a component of the S3:M:E:encapsidated SARS coronavirus genomic RNA: 7a:O-glycosyl 3a tetramer complex.