Toll Like Receptor 7/8 (TLR7/8) Cascade

Stable Identifier
R-HSA-168181
Type
Pathway
Species
Homo sapiens
Related Species
Influenza A virus, Human immunodeficiency virus 1, Human SARS coronavirus
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RNA can serve as a danger signal, both in its double-stranded form as well as single-stranded RNA (ssRNA). Toll like receptor 7 (TLR7) and TLR8 are endosomal receptors that sense ssRNA oligonucleotides containing guanosine (G)- and uridine (U)-rich sequences from RNA viruses (Jurk M et al. 2002; Heil F et al. 2004; Diebold SS et al. 2004; Li Y et al. 2013; reviewed in Lester SN & Li K 2014). TLR7 is primarily expressed in plasmacytoid dendritic cells (pDCs) and, to some extent, in B cells, monocytes and macrophages, whereas TLR8 is mostly expressed in monocytes, macrophages and myeloid DCs. Upon engagement of ssRNAs in endosomes, TLR7/8 initiate the myeloid differentiation factor 88 (MyD88)-dependent pathway, culminating in synthesis of type I and type III IFNs and proinflammatory mediators via activation of IFN regulatory factor 7 (IRF7) and NF-κB, respectively, depending on the cell type (reviewed in Lester SN & Li K 2014). TLR7 and TLR8 are able to detect GU-rich ssRNA sequences from the viral genomes of influenza, human immunodeficiency virus-1 (HIV-1), vesicular stomatitis virus (VSV), coxsackie B virus, coronavirus and flaviviruses (hepatitis C virus, HCV and West Nile virus, WNV; reviewed in Lester SN & Li K 2014). Specifically, GU-rich ssRNA oligonucleotides derived from HIV-1, for example, stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines (Heil F et al. 2004). This has been found to be mediated by TLR7, as well as TLR8. Similarly, severe acute respiratory syndrome-associated coronavirus type 1 (SARS-CoV-1) GU-rich ssRNAs had powerful immunostimulatory activities in mononuclear phagocytes to induce considerable level of pro-inflammatory cytokine TNF-a, IL-6 and IL-12 release via the TLR7 and TLR8 (Li Y et al. 2013). Further, mice deficient in either Tlr7 or the TLR adaptor protein Myd88 demonstrated reduced responses to in vivo infection with VSV (Lund JM et al. 2004), mouse-adapted SARS-CoV-1 (Sheahan et al. 2008; Totura et al., 2015). Upon Middle East respiratory syndrome-related coronavirus (MERS-CoV) infection, lack of MyD88 signaling resulted in delayed viral clearance and increased lung pathology in mice (Zhao et al. 2014). Consistently, another study showed that Tlr7-/- mice have reduced IFN expression compared with wild-type mice (Channappanavar et al. 2019). In addition, loss of function TLR7 variants identified in the patients with SARS-CoV-2 (COVID-19) resulted in defective upregulation of type I IFN–related genes in the TLR7 pathway (Figure 3) in response to the TLR7 agonist imiquimod as compared with controls (Van der Made CI et al. 2020). Separate studies showed that synthetic imidazoquinoline compounds (e.g. imiquimod and R-848, low-molecular-weight immune response modifiers that can induce the synthesis of interferon-alpha) also exert their effects in a MyD88-dependent fashion through TLR7 or TLR8 (Hemmi H et al. 2002; Jurk M et al. 2002; Diebold SS et al. 2004). Some viruses utilize multiple strategies to evade antiviral innate immune signaling, as is seen with influenza or SARS coronaviruses. TLR7-mediated innate immunity, for example, was associated with the negative regulation through removing Lys63-linked polyubiquitin chains of TRAF3/TRAF6 by papin-like protease (PLpro) catalytic domain of nsp3 from SARS-CoV-1 (Li SW et al. 2016). Thus, TLR7 and TLR8 play a critical role in sensing of viral ssRNA in the endosome.

Literature References
PubMed ID Title Journal Year
14976262 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8

Heil, F, Hemmi, H, Hochrein, H, Ampenberger, F, Kirschning, C, Akira, S, Lipford, G, Wagner, H, Bauer, S

Science 2004
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