TBK1 and IRF3 are potential therapeutic targets in Enterovirus A71-associated diseases.
TBK1 and IRF3 are potential therapeutic targets in Enterovirus A71-associated diseases.
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TBK1和IRF3是肠道病毒A71相关疾病的潜在治疗靶点。
DOI：
10.1371/journal.pntd.0011001
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发表时间：
2023-01
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肠道病毒 A71 (EV-A71) 是手足口病 (HFMD) 的重要病原体，与巨大的医疗保健和社会经济负担相关。尽管有关 EV-A71 发病机制的一系列研究已得到充分描述，但先天免疫反应的潜在分子机制仍不完全清楚，特别是 TANK 结合激酶 1 (TBK1) 和干扰素调节因子 3 (IRF3) 的作用。在这里，我们首次应用TBK1抑制剂和IRF3激动剂来评估TBK1和IRF3的体内抗病毒活性。我们发现，通过调节EV-A71诱导的I型干扰素（IFN）反应，IRF3激动剂有效缓解EV-A71诱导的疾病，而TBK1抑制剂则加剧疾病进展。此外，在给予IRF3激动剂的EVA-71感染小鼠中，EV-A71复制受到抑制。另一方面，在接受 TBK1 抑制剂治疗的 EVA-71 感染小鼠中，出现了更严重的神经元变性、肌纤维断裂、肺泡壁断裂或融合以及弥漫性充血等病理改变。此外，我们测定了小鼠肺和脑中白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）、IL-1β、单核细胞趋化蛋白-1（MCP-1）和IL-10的浓度，发现TBK1抑制剂促进EV-A71诱导的炎症反应，而IRF3激动剂减轻炎症反应，这与临床表现和病理改变一致。总的来说，我们的研究结果表明 TBK1 和 IRF3 是 EV-A71 引起的疾病的潜在治疗靶点。 EV-A71是手足口病的重要病原体。目前尚无特效抗病毒药物可治疗手足口病及相关严重并发症。 EV-A71感染后控制宿主先天免疫的潜在分子机制仍不完全清楚，特别是TBK1和IRF3的作用。在这里，我们应用TBK1抑制剂（TBK1/IKKε-IN-2）和IRF3激动剂（KIN1148）来评估TBK1和IRF3的体内抗病毒活性。我们发现，通过调节EV-A71诱导的I型干扰素反应，IRF3激动剂有效缓解EV-A71诱导的疾病，而TBK1抑制剂则加剧疾病进展。 TBK1抑制剂治疗的EVA-71感染小鼠出现更严重的神经元变性、肌纤维断裂、肺泡壁断裂或融合以及弥漫性充血等病理改变，而IRF3激动剂治疗的EVA-71感染小鼠和对照小鼠没有出现明显的病理变化。此外，TBK1抑制剂促进EV-A71诱导的炎症反应，而IRF3激动剂则减轻炎症反应。我们的研究结果表明，TBK1 和 IRF3 是 EV-A71 诱导疾病的潜在治疗靶点，可用于开发新的抗病毒药物和治疗策略。
Enterovirus A71 (EV-A71) is an important causative agent of hand-foot-and-mouth disease (HFMD) associated with enormous healthcare and socioeconomic burden. Although a range of studies about EV-A71 pathogenesis have been well described, the underlying molecular mechanism in terms of innate immune response is still not fully understood, especially the roles of TANK-binding kinase 1 (TBK1) and interferon-regulatory factor 3 (IRF3). Here, we applied TBK1 inhibitor and IRF3 agonist, for the first time, to evaluate the antiviral activities of TBK1 and IRF3 in vivo. We found that, through regulating EV-A71-induced type I interferon (IFN) response, IRF3 agonist effectively alleviated EV-A71-induced illness, while TBK1 inhibitor aggravated disease progression. In addition, EV-A71 replication was suppressed in EVA-71-infected mice administrated with IRF3 agonist. On the other hand, more severe pathological alterations of neuronal degeneration, muscle fiber breaks, fractured or fused alveolar walls, and diffuse congestion occurred in EVA-71-infected mice treated with TBK1 inhibitor administration. Furthermore, we determined the concentrations of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), IL-1β, monocyte chemotactic protein-1 (MCP-1), and IL-10 in both lungs and brains of mice and found that TBK1 inhibitor promoted EV-A71-induced inflammatory response, while IRF3 agonist alleviated it, which was consistent with clinical manifestations and pathological alterations. Collectively, our findings suggest that TBK1 and IRF3 are potential therapeutic targets in EV-A71-induced illness. EV-A71 is an important causative agent of HFMD. There is currently no specific antiviral agent to treat HFMD and the related severe complications. The underlying molecular mechanism controlling host innate immunity after EV-A71 infection is still not fully understood, especially the roles of TBK1 and IRF3. Here, we applied TBK1 inhibitor (TBK1/IKKε-IN-2) and IRF3 agonist (KIN1148) to evaluate the antiviral activities of TBK1 and IRF3 in vivo. We found through regulating EV-A71-induced type I IFN response, IRF3 agonist effectively alleviated EV-A71-induced illness, while TBK1 inhibitor aggravated disease progression. More severe pathological alterations of neuronal degeneration, muscle fiber breaks, fractured or fused alveolar walls and diffuse congestion occurred in EVA-71-infected mice with TBK1 inhibitor treatment, while no obvious pathological change occurred in EVA-71-infected mice with IRF3 agonist treatment and control mice. Furthermore, TBK1 inhibitor promoted EV-A71-induced inflammatory response, while IRF3 agonist alleviated it. Our findings suggest that TBK1 and IRF3 are potential therapeutic targets in EV-A71-induced illness for the development of new antiviral agents and therapeutic strategies.
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DOI：
10.3390/v10010046
发表时间：
2018-01-20
期刊：
Viruses
影响因子：
--
作者：
Ingle H;Peterson ST;Baldridge MT
通讯作者：
Baldridge MT
影响因子：
4.7
作者：
Huang, Hsing-, I;Lin, Jhao-Yin;Chen, Sheng-Hung
通讯作者：
Chen, Sheng-Hung
影响因子：
6.7
作者：
Cordey S;Petty TJ;Schibler M;Martinez Y;Gerlach D;van Belle S;Turin L;Zdobnov E;Kaiser L;Tapparel C
通讯作者：
Tapparel C
白头翁苷 B4 通过上调 14-3-3 表达和 I 型干扰素反应抑制小鼠肠道病毒 71 传播
影响因子：
8.2
作者：
Kang, Nai-xin;Zou, Yue;Yu, Di
通讯作者：
Yu, Di
肠道病毒逃避先天免疫与流行性手足口病有关
影响因子：
5.2
作者：
Jin Y;Zhang R;Wu W;Duan G
通讯作者：
Duan G