西北農林科技大學王晶鈺教授組在小反芻獸疫病毒致病機理方面取得新進展

小反芻獸疫（Peste des petits ruminants，PPR）是由小反芻獸疫病毒（Peste des petits ruminants virus，PPRV）引起的山羊、綿羊等小反芻動物的一種急性烈性高度接觸性傳染病，致死率高。該病被世界動物衛生組織（OIE）列為A類疫病，也是我國規定的Ⅰ類動物疫病。2007年在我國西藏首次發生PPR，2014年先後在青海、寧夏、甘肅、陝西等24個省市自治區暴發，造成了巨大的經濟損失。PPRV病毒感染動物後能引起宿主免疫抑制，但其潛在的致病機制仍不清楚。

西北農林科技大學動物醫學院王晶鈺教授課題組研究發現，PPRV能夠誘導山羊子宮內膜上皮細胞（EECs）發生完全自噬，該病毒能利用細胞自噬增強自身的複製水平。在PPRV感染EECs的過程中，抑制細胞自噬的形成能夠促進Caspase依賴的細胞凋亡，而抑制自噬溶酶體融合過程並不影響細胞的凋亡率。進一步研究發現，PPRV的C、N、H蛋白通過與胞內LC3蛋白共定位可以不同程度誘導宿主細胞自噬的發生。其中C蛋白與IRGM以及N蛋白與HSP70的相互作用是PPRV通過IRGM-HSP70依賴性途徑誘導宿主細胞第二波自噬的關鍵因素。這一原創性成果近日發表在生物學領域權威期刊《Autophagy》（IF=11.059，2018，中科院一區，TOP期刊），題目為「Autophagy induction by the pathogen receptor NECTIN4 and sustained autophagy contribute to peste des petits ruminants virus infectivity」， 西北農林科技大學動物醫學院博士生楊勃，中國獸醫藥品監察所薛青紅研究員為共同第一作者，王晶鈺教授和齊雪峰教授為共同通訊作者。

王晶鈺教授課題組近年來在揭示PPRV的致病機制方面取得了一系列進展，系統研究了小反芻獸疫病毒進入宿主細胞的途徑，受感染細胞內兩波細胞自噬的發生規律和MicroRNA表達譜變化及對病毒複製的調節機制。2018年至今另有4篇相關研究成果先後以 「Binding and entry of peste des petits ruminants virus into caprine endometrial epithelial cells profoundly affect early cellular gene expression 」，「MicroRNA expression profiling of goat peripheral blood mononuclear cells in response to peste des petits ruminants virus infection」，「Peste des Petits Ruminants Virus Enters Caprine Endometrial Epithelial Cells via the Caveolae-Mediated Endocytosis Pathway 」，「Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro.」為題發表在國際權威期刊《Veterinary Research》（IF=3.117，獸醫領域TOP期刊）、《Frontiers in Microbiology》（IF=4.259）、《Virulence》（IF=4.775）。研究成果為揭示小反芻獸疫病毒致病機制和新型疫苗的研發提供了科學依據。

Abstract

Macroautophagy/autophagy is an essential cellular response in the fight against intracellular pathogens. Although some viruses can escape from or utilize autophagy to ensure their own replication, the responses of autophagy pathways to viral invasion remain poorly documented. Here, we show that peste des petits ruminants virus (PPRV) infection induces successive autophagic signalling in host cells via distinct and uncoupled molecular pathways. Immediately upon invasion, PPRV induced a first transient wave of autophagy via a mechanism involving the cellular pathogen receptor NECTIN4 and an AKT-MTOR-dependent pathway. Autophagic detection showed that early PPRV infection not only increased the amounts of autophagosomes and LC3-II but also downregulated the phosphorylation of AKT-MTOR. Subsequently, we found that the binding of viral protein H to NECTIN4 ultimately induced a wave of autophagy and inactivated the AKT-MTOR pathway, which is a critical step for the control of infection. Soon after infection, new autophagic signalling was initiated that required viral replication and protein expression. Interestingly, expression of IRGM and HSPA1A was significantly upregulated following PPRV replication. Strikingly, knockdown of IRGM and HSPA1A expression using small interfering RNAs impaired the PPRV-induced second autophagic wave and viral particle production. Moreover, IRGM-interacting PPRV-C and HSPA1A-interacting PPRV-N expression was sufficient to induce autophagy through an IRGM-HSPA1A-dependent pathway. Importantly, syncytia formation could facilitate sustained autophagy and the replication of PPRV. Overall, our work reveals distinct molecular pathways underlying the induction of self-beneficial sustained autophagy by attenuated PPRV, which will contribute to improving the use of vaccines for therapy.

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