Chauhan Manish, Martinak Peter E, Hollenberg Benjamin M, Goodman Alan G
bioRxiv. 2024 Jun 22:2024.06.19.599730. doi: 10.1101/2024.06.19.599730.
The Toll pathway plays a pivotal role in innate immune responses against pathogens. The evolutionary conserved pathogen recognition receptors (PRRs), including Toll like receptors (TLRs), play a crucial role in recognition of pathogen associated molecular patterns (PAMPs). The genome encodes nine Toll receptors that are orthologous to mammalian TLRs. While mammalian TLRs directly recognize PAMPs, most Tolls recognize the proteolytically cleaved ligand Spätzle to activate downstream signaling cascades. In this study, we demonstrated that Toll-9 is crucial for antiviral immunity against C virus (DCV), a natural pathogen of . A transposable element insertion in the gene renders the flies more susceptible to DCV. The stable expression of Toll-9 in S2 cells confers resistance against DCV infection by upregulation of the RNAi pathway. Toll-9 promotes the dephosphorylation of AKT, resulting in the induction of antiviral RNAi genes to inhibit DCV replication. Toll-9 localizes to the endosome where it binds dsRNA, suggesting its role to detect viral dsRNA. Toll-9 also induces apoptosis during DCV infection, contributing to its antiviral role. Together, this work identifies the role of Toll-9 in antiviral immunity against DCV infection through its ability to bind dsRNA and induce AKT-mediated RNAi antiviral immunity.
Insects rely on innate immunity and RNA interference (RNAi) to combat viral infections. Our study underscores the pivotal role of Toll-9 in antiviral immunity, aligning with findings in , where Toll-9 activation upregulates the RNAi component . We demonstrate that Toll-9 functions as a pattern recognition receptor (PRR) for double-stranded RNA (dsRNA) during virus (DCV) infection, akin to mammalian TLRs. Toll-9 activation leads to the upregulation of key RNAi components, and , and dephosphorylation of AKT triggers apoptosis via induction of proapoptotic genes and . This study also reveals that Toll-9 localizes in endosomal compartments where it interacts with dsRNA. These insights enhance our understanding of innate immune mechanisms, reflecting the evolutionary conservation of immune responses across diverse species and providing impetus for further research into the conserved roles of TLRs across the animal kingdom.
Toll信号通路在针对病原体的先天免疫反应中起关键作用。进化上保守的病原体识别受体（PRRs），包括Toll样受体（TLRs），在识别病原体相关分子模式（PAMPs）中起关键作用。该基因组编码九个与哺乳动物TLRs直系同源的Toll受体。虽然哺乳动物TLRs直接识别PAMPs，但大多数Toll受体识别经蛋白水解切割的配体Spätzle以激活下游信号级联反应。在本研究中，我们证明Toll-9对于抵抗黑腹果蝇的天然病原体蟋蟀麻痹病毒（DCV）的抗病毒免疫至关重要。该基因中的转座子插入使果蝇对DCV更易感。Toll-9在S2细胞中的稳定表达通过上调RNAi途径赋予对DCV感染的抗性。Toll-9促进AKT的去磷酸化，导致抗病毒RNAi基因的诱导以抑制DCV复制。Toll-9定位于内体，在那里它结合双链RNA（dsRNA），表明其检测病毒dsRNA的作用。Toll-9在DCV感染期间也诱导细胞凋亡，有助于其抗病毒作用。总之，这项工作通过其结合dsRNA和诱导AKT介导的RNAi抗病毒免疫的能力确定了Toll-9在抵抗DCV感染的抗病毒免疫中的作用。
昆虫依靠先天免疫和RNA干扰（RNAi）来对抗病毒感染。我们的研究强调了Toll-9在抗病毒免疫中的关键作用，这与黑腹果蝇中的发现一致，其中Toll-9激活上调RNAi成分。我们证明在蟋蟀麻痹病毒（DCV）感染期间，Toll-9作为双链RNA（dsRNA）的模式识别受体（PRR）发挥作用，类似于哺乳动物TLRs。Toll-9激活导致关键RNAi成分的上调，并且AKT的去磷酸化通过诱导促凋亡基因和触发细胞凋亡。这项研究还揭示Toll-9定位于内体区室，在那里它与dsRNA相互作用。这些见解增强了我们对黑腹果蝇先天免疫机制的理解，反映了跨物种免疫反应的进化保守性，并为进一步研究整个动物界TLRs的保守作用提供了动力。
