RSV ssRNA binds C-ter TLR7 dimer

Endosomal recognition of single stranded (ss) RNA occurs by means of toll-like receptor 7 (TLR7) and TLR8 leading to induction of type I and type III interferons and proinflammatory cytokines via a MyD88-mediated signaling pathway (reviewed in Lester SN & Li K 2014; Tatematsu M et al. 2018). Viruses can enter mammalian cells using endosomal or phagosomal pathways delivering their genomes to endosomal compartments (reviewed by Cossart P & Helenius A 2014). For example, entry of respiratory syncytial virus (RSV), a (−)-sense ssRNA virus, occurs through clathrin-mediated endocytosis (Kolokoltsov AA et al. 2007; Krzyzaniak MA et al. 2013). Additionally, autophagy-dependent transfer of viral RNA products from the cytoplasmic viral replication sites into the endosome can trigger the TLR7/8-mediated immune responses (Lee HK et al. 2007). TLR7 likely plays a crucial role in the recognition of RSV. RSV infection upregulates TLR7 expression in human epithelial A549 cells (Dou Y et al. 2013; Sun T et al. 2018) and in the lung tissue of infected mice (Huang S et al. 2009; Lukacs NW et al. 2010). In the mouse model, the TLR7-MyD88 pathway has been found to be essential for the CD8+ T cell response, induction of type I interferon, and proinflammatory cytokines in mouse plasmacytoid dendritic cells (pDCs) during RSV infection (Davidson S et al. 2011; Kim TH et al. 2019). TLR7 or MyD88 deficiency in mice leads to a more severe RSV infection, characterized by mucus production, inflammation, and altered T cell responses with increased production of mucogenic cytokines (Rudd BD et al. 2007; Lukacs NW et al. 2010; Davidson S et al. 2011). Imiquimod, a TLR7 agonist, exhibits direct antiviral activity against RSV and modulates cytokine responses through the PKA pathway in human epithelial Hep-2 and A549 cells, suggesting that the drug may have therapeutic potential in controlling RSV pathogenesis (Salinas FM et al. 2020). Further, Schlender J et al. (2005) showed that RSV can inhibit type I interferon production in human pDCs stimulated with TLR7/9 agonists. <p>This Reactome event shows recognition of RSV ssRNA by TLR7 in the endosome lumen. However, the molecular mechanisms underlying activation/modulation of the TLR7 signaling pathway by RSV are not fully understood.

内体对单链RNA（ssRNA）的识别通过Toll样受体7（TLR7）和TLR8实现，进而通过MyD88介导的信号通路诱导I型和III型干扰素及促炎细胞因子的产生（参见Lester SN & Li K 2014；Tatematsu M等2018年的综述）。病毒可通过内体或吞噬体途径进入哺乳动物细胞，将基因组传递至内体区室（参见Cossart P & Helenius A 2014年的综述）。例如，呼吸道合胞病毒（RSV）这种（-）链单链RNA病毒的进入是通过网格蛋白介导的内吞作用实现的（参见Kolokoltsov AA等2007；Krzyzaniak MA等2013年的研究）。此外，依赖自噬的病毒RNA产物从细胞质病毒复制位点转移到内体中，可以触发TLR7/8介导的免疫反应（参见Lee HK等2007年的研究）。TLR7可能在RSV的识别中发挥关键作用。RSV感染可上调人类上皮细胞A549细胞中TLR7的表达（参见Dou Y等2013；Sun T等2018年的研究），以及感染小鼠肺组织中的TLR7表达（参见Huang S等2009；Lukacs NW等2010年的研究）。在动物模型中，TLR7-MyD88通路已被证明对于RSV感染期间小鼠浆细胞样树突状细胞（pDCs）的CD8+ T细胞反应、I型干扰素诱导和促炎细胞因子的产生是必需的（参见Davidson S等2011；Kim TH等2019年的研究）。小鼠中TLR7或MyD88的缺陷会导致RSV感染更为严重，表现为粘液分泌、炎症以及T细胞反应的改变，粘膜生成细胞因子的产生增加（参见Rudd BD等2007；Lukacs NW等2010；Davidson S等2011年的研究）。咪喹莫特，一种TLR7激动剂，对RSV具有直接的抗病毒活性，并通过PKA通路调节人类上皮细胞Hep-2和A549细胞中的细胞因子反应，这表明该药物在控制RSV发病机制方面可能具有治疗潜力（参见Salinas FM等2020年的研究）。此外，Schlender J等（2005）的研究表明，RSV可以抑制受TLR7/9激动剂刺激的人类pDCs中I型干扰素的产生。《Reactome事件》显示，RSV ssRNA在内体腔内被TLR7识别。然而，RSV激活/调节TLR7信号通路的分子机制尚不完全明了。