TLR8 dimer binds SARS-CoV-2 GU-rich ssRNA

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
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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 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). In human macrophages, GU-rich RNA derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 triggered TLR8-mediated pro-inflammatory responses leading to activation of the NLRP3 inflammasome and IL-1β secretion (Campbell GR et al. 2021). In human monocyte-derived DCs, TLR8 recognized SARS-CoV-2 ssRNA (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).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 TLR8 and SARS-CoV-2 ssRNA.

Literature References
PubMed ID Title Journal Year
33718825 SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway

Campbell, GR, Hanna, J, To, RK, Spector, SA

iScience 2021
34375313 SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8

Laffranchi, M, Garlanda, C, Schioppa, T, Sozio, F, Salvi, V, Tamassia, N, Scapini, P, Sozzani, S, Nguyen, HO, Del Prete, A, Cassatella, MA, Bosisio, D, Mantovani, A, Tiberio, L, Barbazza, I, Gaudenzi, C, Passari, M

JCI Insight 2021
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