Influenza A virus activates cellular Tropomyosin receptor kinase A (TrkA) signaling to promote viral replication and lung inflammation.
Influenza A virus activates cellular Tropomyosin receptor kinase A (TrkA) signaling to promote viral replication and lung inflammation.
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DOI：
10.1371/journal.ppat.1010874
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发表时间：
2022-09
期刊：
影响因子：
6.7
通讯作者：
Liang, Yuying
中科院分区：
文献类型：
--
作者：
Verma, Vikram;Dileepan, Mythili;Huang, Qinfeng;Phan, Thu;Hu, Wei-Shou;Ly, Hinh;Liang, Yuying
甲型流感病毒（IAV）感染引起急性呼吸道疾病，具有潜在的严重和致命的并发症。病毒的发病机制不仅是由于病毒感染的直接细胞病变效应，而且还由于宿主炎症反应的加剧。流感病毒感染可激活多种宿主信号传导途径，其功能是激活或抑制病毒复制。我们以前的研究表明，受体酪氨酸激酶TrkA在体外流感病毒的复制中起着重要的作用，但其在流感病毒感染中的生物学作用和功能机制尚未得到表征。在这里，我们表明，IAV感染强烈激活TrkA在体外和体内。在TrkA基因敲入（TrkA KI）小鼠模型中使用化学遗传学方法通过小分子化合物1 NMPP 1特异性控制TrkA激酶活性，我们表明1 NMPP 1介导的TrkA抑制通过显著降低病毒载量和肺部炎症完全保护小鼠免受致死性IAV感染。使用从TrkA KI小鼠中分离的原代肺细胞，我们表明特异性TrkA抑制减少了气道上皮细胞（AEC）中的IAV病毒RNA合成，但在肺泡巨噬细胞（AM）中没有。转录组学分析证实了TrkA在病毒RNA合成中的细胞类型特异性作用，并在IAV感染的AEC和AM中鉴定了TrkA调控下的不同基因表达模式。在TrkA激活的靶标中有各种促炎细胞因子和趋化因子，如IL 6、IL-1β、IFN、CCL-5和CXCL 9，支持TrkA在介导肺部炎症中的作用。事实上，虽然在IAV复制高峰后给予TrkA抑制剂1 NMPP 1对病毒载量没有影响，但它能够减少肺部炎症并在小鼠中提供部分保护。综上所述，我们的研究结果首次证明了TrkA信号在IAV感染中的重要生物学作用，确定了其对病毒复制的细胞类型特异性贡献，并揭示了其在病毒诱导的肺部炎症中的功能机制。这项研究表明，TrkA作为一种新的宿主靶点，用于针对流感病毒疾病的治疗开发。尽管每年都有疫苗接种计划和几种抗病毒选择，但流感病毒继续导致每年的流行病，偶尔的人畜共患病感染和人类大流行。需要有效的抗病毒治疗来对抗严重的流感呼吸道疾病，其由直接的病毒细胞病变效应和加剧的宿主炎症反应引起。在这项研究中，我们表明，宿主受体酪氨酸激酶TrkA信号是功能上重要的促进流感病毒复制和病毒诱导的肺部炎症。利用一种独特的小鼠模型及其衍生的原代肺细胞，其中TrkA激酶活性可以被一种小的化合物抑制剂特异性地控制，我们证明了TrkA在动物流感病毒感染中的重要作用，并揭示了其在促进病毒复制和肺部炎症中的细胞类型特异性功能机制。我们的研究表明，TrkA作为一个潜在的新的宿主靶点，开发有效的治疗流感病毒性疾病。
Influenza A virus (IAV) infection causes acute respiratory disease with potential severe and deadly complications. Viral pathogenesis is not only due to the direct cytopathic effect of viral infections but also to the exacerbated host inflammatory responses. Influenza viral infection can activate various host signaling pathways that function to activate or inhibit viral replication. Our previous studies have shown that a receptor tyrosine kinase TrkA plays an important role in the replication of influenza viruses in vitro, but its biological roles and functional mechanisms in influenza viral infection have not been characterized. Here we show that IAV infection strongly activates TrkA in vitro and in vivo. Using a chemical-genetic approach to specifically control TrkA kinase activity through a small molecule compound 1NMPP1 in a TrkA knock-in (TrkA KI) mouse model, we show that 1NMPP1-mediated TrkA inhibition completely protected mice from a lethal IAV infection by significantly reducing viral loads and lung inflammation. Using primary lung cells isolated from the TrkA KI mice, we show that specific TrkA inhibition reduced IAV viral RNA synthesis in airway epithelial cells (AECs) but not in alveolar macrophages (AMs). Transcriptomic analysis confirmed the cell-type-specific role of TrkA in viral RNA synthesis, and identified distinct gene expression patterns under the TrkA regulation in IAV-infected AECs and AMs. Among the TrkA-activated targets are various proinflammatory cytokines and chemokines such as IL6, IL-1β, IFNs, CCL-5, and CXCL9, supporting the role of TrkA in mediating lung inflammation. Indeed, while TrkA inhibitor 1NMPP1 administered after the peak of IAV replication had no effect on viral load, it was able to decrease lung inflammation and provided partial protection in mice. Taken together, our results have demonstrated for the first time an important biological role of TrkA signaling in IAV infection, identified its cell-type-specific contribution to viral replication, and revealed its functional mechanism in virus-induced lung inflammation. This study suggests TrkA as a novel host target for therapeutic development against influenza viral disease. Despite the annual vaccination program and several antiviral options, influenza viruses continue to cause annual epidemics, occasional zoonotic infections and pandemics in humans. Effective antiviral therapeutics are needed to combat severe influenza respiratory disease, which is caused by both the direct viral cytopathic effect and the exacerbated host inflammatory responses. In this study, we show that a host receptor tyrosine kinase TrkA signaling is functionally important for promoting both influenza viral replication and virus-induced lung inflammation. Using a unique mouse model and its derived primary lung cells, in which the TrkA kinase activity can be specifically controlled by a small compound inhibitor, we demonstrated the important role of TrkA in the influenza A viral infection in animals and revealed its cell-type-specific functional mechanisms in promoting viral replication and lung inflammation. Our study suggests TrkA as a potential novel host target for developing effective therapeutics against influenza viral diseases.
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影响因子：
12.3
作者：
Huang, Da Wei;Sherman, Brad T;Tan, Qina;Collins, Jack R;Alvord, W Gregory;Roayaei, Jean;Stephens, Robert;Baseler, Michael W;Lane, H Clifford;Lempicki, Richard A
通讯作者：
Lempicki, Richard A
DOI：
10.1038/s41572-018-0002-y
发表时间：
2018-06-28
期刊：
Nature reviews. Disease primers
影响因子：
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