Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands

Zhang, Zhikuan; Ohto, Umeharu; Shibata, Takuma; Taoka, Masato; Yamauchi, Yoshio; Sato, Ryota; Shukla, Nikunj M.; David, Sunil A.; Isobe, Toshiaki; Miyake, Kensuke; Shimizu, Toshiyuki

doi:10.1016/j.celrep.2018.11.081

Cited by 113 publications

(110 citation statements)

References 45 publications

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“…The TLR7 ligand CL264 induced lower levels of IL-6 than TLR8 ligands while the TLR9 ligand CpG showed no effect or even decreased cytokine secretion induced by TCR activation of the T cells. CL264 is a synthetic TLR7 ligand (adenine analog) and we cannot guarantee that it does not show some cross reactivity to TLR8 70 . The TLR8 inhibitors CU-CPT9a and CU-CPT9b successfully inhibited the cytokine responses to TLR8 ligands and to endosomal HIV, suggesting HIV ssRNA is engaging TLR8.…”

Section: Discussionmentioning

confidence: 95%

“…The natural ligands for TLR7 and 8 are ssRNAs in the forms of degradation products, nucleosides (guanosine and uridine, respectively), and oligoribonucleotides engaging different binding pockets. CL75, CL264, and R837 are synthetic imidazoquinolinone derivatives (IQDs) that are able to strongly interact with TLR7 and 8 homodimers and activate signaling in the absence of oligonucleotides, which are believed to function mainly to enhance the binding affinities of the nucleosides/IQDs 70,[75][76][77] . PolyU is solely capable of activating TLR8, but interactions are stronger if combined with degradation products (uridine, endogenous nucleoside derivatives or IQDs).…”

Section: Discussionmentioning

confidence: 99%

“…Both polyU and CL75 are considered more specific activators of TLR8 than TLR7. However, structural binding studies show that some cross-specificity is possible 70 . Although differences in potency was expected, we were surprised by the consistent differences observed between CL75 and polyU: polyU was most efficient in HIV reactivation and in upregulation of T cell activation markers whereas CL75 was most potent in enhancing HIV replication.…”

Section: Discussionmentioning

confidence: 99%

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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

et al. 2020

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During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

et al. 2020

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“…Although some characterization of their ligand recognition specificities has been performed (1-3), there is still only minimal knowledge about the endogenously occurring molecules that activate these receptors. This is notable, as responses driven by activation of these receptors may be different if the stimulus is a synthetic small molecule or larger RNA species (1,4,5). Although TLR7 and TLR8 likely evolved to be sensors of foreign viral RNA, they may also respond to endogenous RNA molecules and drive Type I IFN production, inflammation, and autoimmunity associated with diseases such as systemic lupus erythematosus (SLE) in which autoantibodies and immune complexes containing RNA molecules are generated (6).…”

Section: Introductionmentioning

confidence: 99%

TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation

et al. 2020

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TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 are normally part of the antiviral defense response, but they have also been implicated as drivers of autoimmune diseases such as lupus. The receptors have slightly different ligand-binding specificities and cellular expression patterns that suggest they have nonredundant specialized roles. How the roles of TLR7 and TLR8 differ may be determined by which cell types express each TLR and how the cells respond to activation of each receptor. To provide a better understanding of the effects of TLR7/8 activation, we have characterized changes induced by TLR-specific agonists in different human immune cell types and defined which responses are a direct consequence of TLR7 or TLR8 activation and which are secondary responses driven by type I IFN or cytokines produced subsequent to the primary response. Using cell sorting, gene expression analysis, and intracellular cytokine staining, we have found that the IFN regulatory factor (IRF) and NF-kB pathways are differentially activated downstream of the TLRs in various cell types. Studies with an anti-IFNAR Ab in human cells and lupus mice showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-kB-regulated genes induced directly by TLR7/8 activation at earlier timepoints. In summary, these results elucidate the different roles TLR7 and TLR8 play in immunity and inform strategies for potential treatment of autoimmune diseases driven by TLR7/8 activation. ImmunoHorizons, 2020, 4: 93-107.

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“…At the same time, TLR8 is expressed by myeloid DC (mDC) and macrophages in humans [ 89 ]. TLR7 has been shown to detect single-stranded RNA (ssRNA), polyuridine, as well as synthetic ssRNA rich in uridine along with guanosine [ 90 ]. Similarly, TLR8 recognizes AU-rich and GU-rich ssRNA, and RNA viruses also trigger it.…”

Section: Activation Of the Innate Immune Systemmentioning

confidence: 99%

Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside

et al. 2020

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The RNA interference (RNAi) pathway possesses immense potential in silencing any gene in human cells. Small interfering RNA (siRNA) can efficiently trigger RNAi silencing of specific genes. FDA Approval of siRNA therapeutics in recent years garnered a new hope in siRNA therapeutics. However, their therapeutic use is limited by several challenges. siRNAs, being negatively charged, are membrane-impermeable and highly unstable in the systemic circulation. In this review, we have comprehensively discussed the extracellular barriers, including enzymatic degradation of siRNAs by serum endonucleases and RNAases, rapid renal clearance, membrane impermeability, and activation of the immune system. Besides, we have thoroughly described the intracellular barriers such as endosomal trap and off-target effects of siRNAs. Moreover, we have reported most of the strategies and techniques in overcoming these barriers, followed by critical comments in translating these molecules from bench to bedside.

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Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands

Cited by 113 publications

References 45 publications

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation

Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside

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