非洲豬瘟(ASF)是豬的一種具有高度傳染性和致死性的烈性傳染病，在我國被列為一類動物疫病。ASF基因組有180 kb，可編碼150-200種蛋白質(zhì)，且有一半以上的蛋白功能尚不清楚。由于ASFV 結(jié)構(gòu)復(fù)雜，病毒感染和免疫機(jī)制不清，所以市場上還沒有商品化疫苗。近年來報(bào)道ASFV基因缺失疫苗可以提供完全保護(hù)作用，因此是目前最具開發(fā)潛力的疫苗。

 

　　2021年，彭貴青教授團(tuán)隊(duì)聯(lián)合中國農(nóng)業(yè)科學(xué)院上海獸醫(yī)研究所探究了抑制宿主蛋白合成的非洲豬瘟基因，闡明E66L是通過跨膜區(qū)（13-34 aa）調(diào)控PKR/eIF2α通路來抑制宿主蛋白的翻譯（Journal of Virology, 2021）。最新的合作研究成果又揭開了ASFV一層新的面紗：I73R基因在ASFV感染早期定位在細(xì)胞核中，發(fā)揮核酸結(jié)合特性，阻止宿主高GC成分的mRNA出核，從而廣泛抑制宿主抗病毒蛋白的合成。體內(nèi)致病性研究顯示，缺失I73R基因的重組病毒具有良好的生物安全性和免疫有效性。上述研究結(jié)果為深入理解非洲豬瘟病毒致病性和免疫逃逸機(jī)制提供了新的理論基礎(chǔ)，為非洲豬瘟缺失疫苗的研發(fā)提供了新的思路。

 

　　該研究得到國家自然科學(xué)基金（32170161；U19A2039；U20A2059；32102652）、國家重點(diǎn)研發(fā)專項(xiàng)（2021YFD1801401；2021YFD1801300；2021YFD1800104）、上海市青年科技英才楊帆計(jì)劃（23YF1457400）、中國農(nóng)業(yè)科學(xué)院農(nóng)業(yè)科學(xué)技術(shù)創(chuàng)新項(xiàng)目（CAAS-ZDRW202203）和中央公益性科研單位基礎(chǔ)研究基金（Y2022PT11）等項(xiàng)目資助。上海獸醫(yī)研究所劉英楠博士和華中農(nóng)業(yè)大學(xué)沈洲博士為論文共同第一作者，上海獸醫(yī)研究所陳鴻軍研究員、華中農(nóng)業(yè)大學(xué)彭貴青教授和華南農(nóng)業(yè)大學(xué)王衡副教授為論文共同通訊作者。

 

　　審核人：彭貴青

 

　　【英文摘要】

 

　　African swine fever virus (ASFV) is a large, double-stranded DNA virus that causes a fatal disease in pigs, posing a threat to the global pig industry. Whereas some ASFV proteins have been found to play important roles in ASFV-host interaction, the functional roles of many proteins are still largely unknown. In this study, we identified I73R, an early viral gene in the replication cycle of ASFV, as a key virulence factor. Our findings demonstrate that pI73R suppresses the host innate immune response by broadly inhibiting the synthesis of host proteins, including antiviral proteins. Crystallization and structural characterization results suggest that pI73R is a nucleic-acid-binding protein containing a Zα domain. It localizes in the nucleus and inhibits host protein synthesis by suppressing the nuclear export of cellular messenger RNA (mRNAs). While pI73R promotes viral replication, the deletion of the gene showed that it is a nonessential gene for virus replication. In vivo safety and immunogenicity evaluation results demonstrate that the deletion mutant ASFV-GZΔI73R is completely nonpathogenic and provides effective protection to pigs against wild-type ASFV. These results reveal I73R as a virulence-related gene critical for ASFV pathogenesis and suggest that it is a potential target for virus attenuation. Accordingly, the deletion mutant ASFV-GZΔI73R can be a potent live-attenuated vaccine candidate

 

　　原文鏈接：https://pubmed.ncbi.nlm.nih.gov/37023125/

 

　　https://pubmed.ncbi.nlm.nih.gov/33328305/