The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection.
The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection.
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DOI：
10.1080/22221751.2022.2164217
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发表时间：
2023-12
影响因子：
13.2
通讯作者：
中科院分区：
文献类型：
--
作者：
CSFV（经典猪瘟病毒）目前在亚洲发展中国家流行，最近在日本重新出现。在自然选择的压力下，猪瘟病毒不断进化以维持其在自然界中的生态位。CSFV已进化出诱导免疫抑制的机制，但其致病机制仍不清楚。在这项研究中，使用转录组学和代谢组学方法，我们发现CSFV感染通过激活干扰素途径，抑制宿主炎症，细胞凋亡和重塑宿主在猪肺泡巨噬细胞中的代谢来改变宿主的先天免疫。此外，我们发现自噬可以改变CSFV感染诱导的天然免疫和代谢。增强的自噬进一步抑制CSFV诱导的RIG-I-IRF3信号转导轴和JAK-STAT信号通路，并阻断I型干扰素的产生，同时减少自噬对NF-κ B信号通路的抑制和CSFV感染细胞的凋亡。此外，CSFV感染诱导的糖酵解水平和乳酸和丙酮酸的含量，以及3-磷酸甘油醛，糖酵解转化为丝氨酸的衍生物，被自噬改变。我们还发现，沉默糖酵解代谢限速酶HK 2（己糖激酶2）可诱导自噬，但降低干扰素信号通路和NF-κ B信号通路，并抑制CSFV感染诱导的细胞凋亡。此外，通过沉默ATG 5或使用3-甲基腺嘌呤抑制细胞自噬，可以回填沉默HK 2对细胞干扰素信号通路、NF-κ B信号通路和细胞凋亡的抑制作用。
CSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodelling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signalling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signalling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signalling pathway, NF-κB signalling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signalling pathway, NF-κB signalling pathway, and apoptosis.
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