Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Virol. 2018 Oct 12;92(21). doi: 10.1128/JVI.01325-18. Print 2018 Nov 1.
Influenza virus outbreaks remain a serious threat to public health. A greater understanding of how cells targeted by the virus respond to the infection can provide insight into the pathogenesis of disease. Here we examined the transcriptional profile of -infected and uninfected type 2 alveolar epithelial cells (AEC) in the lungs of influenza virus-infected mice. We show for the first time the unique gene expression profiles induced by the infection of AEC as well as the transcriptional response of uninfected bystander cells. This work allows us to distinguish the direct and indirect effects of infection at the cellular level. Transcriptome analysis revealed that although directly infected and bystander AEC from infected animals shared many transcriptome changes compared to AEC from uninfected animals, directly infected cells produce more interferon and express lower levels of Wnt signaling-associated transcripts, while concurrently expressing more transcripts associated with cell death pathways, than bystander uninfected AEC. The Wnt signaling pathway was downregulated in both -infected AEC and -infected human lung epithelial A549 cells. Wnt signaling did not affect type I and III interferon production by infected A549 cells. Our results reveal unique transcriptional changes that occur within infected AEC and show that influenza virus downregulates Wnt signaling. In light of recent findings that Wnt signaling is essential for lung epithelial stem cells, our findings reveal a mechanism by which influenza virus may affect host lung repair. Influenza virus infection remains a major public health problem. Utilizing a recombinant green fluorescent protein-expressing influenza virus, we compared the transcriptomes of directly infected and uninfected bystander cells from infected mouse lungs and discovered many pathways uniquely regulated in each population. The Wnt signaling pathway was downregulated in directly infected cells and was shown to affect virus but not interferon production. Our study is the first to discern the transcriptome changes induced by direct viral infection compared to mere exposure to the lung inflammatory milieu and highlight the downregulation of Wnt signaling. This downregulation has important implications for understanding influenza virus pathogenesis, as Wnt signaling is critical for lung epithelial stem cells and lung epithelial cell differentiation. Our findings reveal a mechanism by which influenza virus may affect host lung repair and suggest interventions that prevent damage or accelerate recovery of the lung.
流感病毒的爆发仍然是对公共卫生的严重威胁。更深入地了解病毒靶向的细胞对感染的反应，可以深入了解疾病的发病机制。在这里，我们研究了感染流感病毒的小鼠肺部中受感染和未受感染的 2 型肺泡上皮细胞（AEC）的转录谱。我们首次展示了由 AEC 感染引起的独特基因表达谱，以及未受感染的旁观者细胞的转录反应。这项工作使我们能够在细胞水平上区分感染的直接和间接影响。转录组分析显示，尽管与来自未感染动物的 AEC 相比，来自感染动物的直接感染和旁观者 AEC 具有许多转录组变化，但直接感染的细胞产生更多的干扰素，并且表达较低水平的 Wnt 信号相关转录物，同时表达更多与细胞死亡途径相关的转录物，而不是旁观者未受感染的 AEC。Wnt 信号通路在感染的 AEC 和感染的人肺上皮 A549 细胞中均下调。Wnt 信号通路不影响感染的 A549 细胞中 I 型和 III 型干扰素的产生。我们的结果揭示了感染的 AEC 中发生的独特转录变化，并表明流感病毒下调了 Wnt 信号通路。鉴于最近发现 Wnt 信号通路对肺上皮干细胞至关重要，我们的研究结果揭示了流感病毒可能影响宿主肺修复的一种机制。流感病毒感染仍然是一个主要的公共卫生问题。我们利用表达重组绿色荧光蛋白的流感病毒，比较了来自感染小鼠肺部的直接感染和未受感染的旁观者细胞的 转录组，发现了许多在每个群体中独特调节的途径。Wnt 信号通路在直接感染的细胞中下调，并显示出影响病毒但不影响干扰素产生。我们的研究首次区分了直接病毒感染引起的转录组变化与仅仅暴露于肺部炎症环境引起的变化，并强调了 Wnt 信号通路的下调。这种下调对于理解流感病毒发病机制具有重要意义，因为 Wnt 信号通路对于肺上皮干细胞和肺上皮细胞分化至关重要。我们的研究结果揭示了流感病毒可能影响宿主肺修复的一种机制，并提出了预防肺损伤或加速肺恢复的干预措施。
