Endosomal recognition of viral single stranded (ss) RNA occurs by means of toll-like receptor 7 (TLR7) and TLR8. TLR7 and TLR8 detect GU-rich ssRNA sequences from the viral genomes of orthomyxovirus (influenza A), lentivirus (human immunodeficiency virus-1, HIV-1), vesiculovirus (vesicular stomatitis virus, VSV), enterovirus (coxsackie B virus), flavivirus (HCV and WNV) and betacoronavirus (severe acute respiratory syndrome-associated coronavirus type 1, SARS-CoV-1 and type 2, SARS-CoV-2) (Hemmi H et al. 2002; Jurk M et al. 2002; Diebold SS et al. 2004; Heil F et al. 2004; Cervantes-Barragan L et al. 2007; Li Y et al. 2013; Scheuplein VA et al. 2015; Campbell GR et al. 2021; reviewed in Lester SN & Li K 2014). Specifically, GU-rich ssRNA derived from SARS‑CoV‑1 induced mononuclear phagocytes to release considerable levels of pro‑inflammatory cytokines TNF‑a, IL‑6 and IL‑12 via TLR7 and TLR8 (Li Y et al. 2013). Bioinformatics scanning techniques showed that the SARS‑CoV‑2 genome contains a large number of fragments that could be recognized by TLR7/TLR8 (Moreno‑Eutimio MA et al. 2020; Salvi V et al. 2021). SARS-CoV-2 ssRNA increased NF-kappaB luciferase reporter activity in TLR7 or TLR8-expressing human embryonic kidney 293 (HEK293T) cells (Salvi V et al. 2021). In addition, NF-kappaB phosphorylation was reduced by TLR7 inhibitor Pepinh-MYD and TLR7-specific siRNA in a lung multicellular spheroid model formed by human lung epithelial Calu-3 cells and human lung-derived fibroblasts MRC-5 (Bortolotti D et al. 2021). TLR7 is thought to recognize SARS-CoV-2 ssRNA in human plasmacytoid DCs (pDCs) (Salvi V et al. 2021). These results are consistent with studies showing that SARS-CoV-2 infection induces activation of human pDC via IRAK4 and UNC93B1, the molecules involved in the endosomal TLR7, TLR8 and TLR9 signaling pathways (Onodi F et al. 2021). Further, inborn TLR7 variants are associated with impaired IFN responses in COVID-19 patients (van der Made CI et al. 2020; Asano T et al. 2021). These data suggest that TLR7 is activated by SARS-CoV-2 ssRNA. Upon engagement of ssRNAs in endosomes, TLR7 and TLR8 initiate the MyD88‑dependent pathway, leading to production of type I and type III IFNs and proinflammatory mediators via activation of IRF7 and NF‑κB, respectively (reviewed in Lester SN & Li K 2014). Although TLR7 and TLR8 share structural homology and both sense viral GU-rich ssRNA, their binding affinities to TLR7/TLR8 ligands may differ (Li Y et al. 2013; Campbell GR et al. 2021). TLR7‑specific ligands generally induce IFN‑regulated cytokines, but TLR8‑specific ligands lead primarily to the production of proinflammatory cytokines (Gorden KB et al. 2005).

This Reactome event shows interaction between human TLR7 and SARS-CoV-2 ssRNA.