The Japanese encephalitis virus (JEV) is a Culex mosquito-borne flavivirus and is the pathogenic agent of Japanese encephalitis, which is the most important type of viral encephalitis in the world. Macrophages are a type of pivotal innate immunocyte that serve as sentinels and respond quickly to pathogen invasions. However, some viruses like JEV can hijack macrophages as a refuge for viral replication and immune escape. Despite their crucial involvement in early JEV infection, the transcriptomic landscapes of JEV-infected macrophages are void. Here, by using an in situ JEV infection model, we investigate the transcriptomic alteration of JEV-infected peritoneal macrophages. We found that, upon JEV infection, the macrophages underwent M1 polarization and showed the drastic activation of innate immune and inflammatory pathways. Interestingly, almost all the programmed cell death (PCD) pathways were activated, especially the apoptosis, pyroptosis, and necroptosis pathways, which were verified by the immunofluorescent staining of specific markers. Further transcriptomic analysis and TUNEL staining revealed that JEV infection caused apparent DNA damage. The transcriptomic analysis also revealed that JEV infection promoted ROS and RNS generation and caused oxidative stress, which activated multiple cell death pathways. Our work uncovers the pivotal pathogenic roles of oxidative stress and multiple PCD pathways in JEV infection, providing a novel perspective on JEV-host interactions.

中文翻译：

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转录组学分析表明，在日本脑炎病毒感染的巨噬细胞中，M1极化和多种程序性细胞死亡途径的启动。

日本脑炎病毒（JEV）是库蚊蚊媒黄病毒，是日本脑炎的病原体，日本脑炎是世界上最重要的病毒性脑炎。巨噬细胞是一种关键的先天免疫细胞，可以作为前哨，并对病原体的入侵做出快速反应。但是，某些病毒（如JEV）可以劫持巨噬细胞，作为病毒复制和免疫逃逸的避难所。尽管他们参与了早期的JEV感染，但JEV感染的巨噬细胞的转录组情况却是无效的。在这里，通过使用原位JEV感染模型，我们调查了JEV感染的腹膜巨噬细胞的转录组学变化。我们发现，在JEV感染后，巨噬细胞经历了M1极化并显示出先天免疫和炎性途径的急剧活化。有趣的是 几乎所有的程序性细胞死亡（PCD）途径均被激活，尤其是凋亡，焦磷酸化和坏死性凋亡途径，这些均已通过特异性标记物的免疫荧光染色进行了验证。进一步的转录组分析和TUNEL染色显示JEV感染引起了明显的DNA损伤。转录组分析还显示，JEV感染促进了ROS和RNS的产生并引起氧化应激，从而激活了多个细胞死亡途径。我们的工作揭示了在JEV感染中氧化应激和多种PCD途径的关键致病作用，为JEV与宿主之间的相互作用提供了新的视角。进一步的转录组分析和TUNEL染色显示JEV感染引起了明显的DNA损伤。转录组分析还显示，JEV感染促进了ROS和RNS的生成并引起氧化应激，从而激活了多个细胞死亡途径。我们的工作揭示了在JEV感染中氧化应激和多种PCD途径的关键致病作用，为JEV与宿主之间的相互作用提供了新的视角。进一步的转录组分析和TUNEL染色显示JEV感染引起了明显的DNA损伤。转录组分析还显示，JEV感染促进了ROS和RNS的生成并引起氧化应激，从而激活了多个细胞死亡途径。我们的工作揭示了在JEV感染中氧化应激和多种PCD途径的关键致病作用，为JEV与宿主之间的相互作用提供了新的视角。