A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.
A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.
复制标题
DOI：
10.1128/mbio.00452-17
复制
发表时间：
2017-05-02
期刊：
影响因子：
6.4
通讯作者：
DeFilippis VR
中科院分区：
文献类型：
--
作者：
Pryke KM;Abraham J;Sali TM;Gall BJ;Archer I;Liu A;Bambina S;Baird J;Gough M;Chakhtoura M;Haddad EK;Kirby IT;Nilsen A;Streblow DN;Hirsch AJ;Smith JL;DeFilippis VR
拉丁美洲和加勒比地区当前同时爆发的寨卡病毒、基孔肯雅热病毒和登革热病毒凸显了开发广谱抗病毒治疗的必要性。 I 型干扰素 (IFN) 系统在脊椎动物中进化，产生组织反应，主动阻止多种已知和潜在人畜共患病毒的复制。因此，通过药物对其进行控制和激活可能代表一种新的治疗策略，用于同时损害多种病毒类型的生长并使宿主群体对病毒传播具有抵抗力。鉴于该策略的潜力，我们进行了筛选，以确定新型干扰素激活小分子。在这里，我们描述了 1-(2-氟苯基)-2-(5-异丙基-1,3,4-噻二唑-2-基)-1,2-二氢苯并[2,3-c]吡咯-3,9-二酮，我们将其称为 AV-C。用 AV-C 处理人类细胞会激活先天反应和干扰素相关反应，从而强烈抑制寨卡病毒、基孔肯雅病毒和登革热病毒的复制。通过利用基因组编辑，我们研究了 AV-C 诱导的细胞状态所必需的宿主蛋白。这表明该化合物需要 TRIF 依赖性信号级联，最终导致 IFN 调节因子 3 (IRF3) 依赖性 I 型干扰素的表达和分泌，从而引发抗病毒反应。其他典型的 IRF3 末端接头蛋白 STING 和 IPS-1/MAVS 对于 AV-C 诱导的表型来说是可有可无的。然而，我们的工作揭示了 IPS-1/MAVS 在黄病毒复制中的重要抑制作用，而不是 TRIF，这意味着 TRIF 引导的病毒逃逸可能不会发生。此外，我们还发现，针对 AV-C，原代人外周血单核细胞会分泌促炎细胞因子，这些细胞因子与针对病毒病原体的适应性免疫的建立有关。最终，AV-C 等合成先天免疫激活剂可用于多种治疗目的，包括直接抗菌反应和促进病原体导向的适应性免疫。 I 型干扰素系统是先天免疫反应的一部分，该反应在脊椎动物中进化而来，是针对未知的微生物（尤其是病毒）病原体多样性的广谱免疫防御的第一道防线。在这里，我们描述了一种新型小分子，它可以人为地激活这种反应，从而产生一种对抗当前新兴病毒（寨卡病毒、基孔肯雅病毒和登革热病毒）生长的细胞状态。我们还表明，该分子能够引发细胞反应，从而预测适应性免疫的建立。因此，该药物可能是对抗新出现的病毒性疾病和其他病毒性疾病的强大且多管齐下的治疗工具。
The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.