Cuesta-Geijo Miguel Ángel, Chiappi Michele, Galindo Inmaculada, Barrado-Gil Lucía, Muñoz-Moreno Raquel, Carrascosa José L, Alonso Covadonga
Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain.
Department of Structure of Macromolecules, Centro Nacional de Biotecnología, Universidad Autónoma de Madrid, Madrid, Spain.
J Virol. 2015 Nov 25;90(3):1534-43. doi: 10.1128/JVI.02694-15. Print 2016 Feb 1.
African swine fever virus (ASFV) is a major threat for porcine production that has been slowly spreading in Eastern Europe since its first appearance in the Caucasus in 2007. ASFV enters the cell by endocytosis and gains access to the cytosol to start replication from late endosomes and multivesicular bodies. Cholesterol associated with low-density lipoproteins entering the cell by endocytosis also follows a trafficking pathway similar to that of ASFV. Here we show that cholesterol plays an essential role in the establishment of infection as the virus traffics through the endocytic pathway. In contrast to the case for other DNA viruses, such as vaccinia virus or adenovirus 5, cholesterol efflux from endosomes is required for ASFV release/entry to the cytosol. Accumulation of cholesterol in endosomes impairs fusion, resulting in retention of virions inside endosomes. ASFV also remodels intracellular cholesterol by increasing its cellular uptake and redistributes free cholesterol to viral replication sites. Our analysis reveals that ASFV manipulates cholesterol dynamics to ensure an appropriate lipid flux to establish productive infection.
Since its appearance in the Caucasus in 2007, African swine fever (ASF) has been spreading westwards to neighboring European countries, threatening porcine production. Due to the lack of an effective vaccine, ASF control relies on early diagnosis and widespread culling of infected animals. We investigated early stages of ASFV infection to identify potential cellular targets for therapeutic intervention against ASF. The virus enters the cell by endocytosis, and soon thereafter, viral decapsidation occurs in the acid pH of late endosomes. We found that ASFV infection requires and reorganizes the cellular lipid cholesterol. ASFV requires cholesterol to exit the endosome to gain access to the cytoplasm to establish productive replication. Our results indicate that there is a differential requirement for cholesterol efflux for vaccinia virus or adenovirus 5 compared to ASFV.
非洲猪瘟病毒（ASFV）是猪生产的主要威胁，自2007年在高加索地区首次出现以来，一直在东欧缓慢传播。ASFV通过内吞作用进入细胞，并进入细胞质，从晚期内体和多囊泡体开始复制。通过内吞作用进入细胞的与低密度脂蛋白相关的胆固醇也遵循与ASFV相似的运输途径。在这里，我们表明胆固醇在病毒通过内吞途径运输时在感染的建立中起着至关重要的作用。与其他DNA病毒（如痘苗病毒或腺病毒5）的情况不同，ASFV释放/进入细胞质需要胆固醇从内体流出。胆固醇在内体中的积累会损害融合，导致病毒粒子保留在内体中。ASFV还通过增加其细胞摄取来重塑细胞内胆固醇，并将游离胆固醇重新分布到病毒复制位点。我们的分析表明，ASFV操纵胆固醇动态以确保适当的脂质通量以建立有效的感染。
自2007年在高加索地区出现以来，非洲猪瘟（ASF）一直在向西蔓延到邻近的欧洲国家，威胁着猪的生产。由于缺乏有效的疫苗，ASF的控制依赖于早期诊断和对感染动物的广泛扑杀。我们研究了ASFV感染的早期阶段，以确定针对ASF进行治疗干预的潜在细胞靶点。病毒通过内吞作用进入细胞，此后不久，病毒脱壳发生在晚期内体的酸性pH值中。我们发现ASFV感染需要并重组细胞脂质胆固醇。ASFV需要胆固醇离开内体以进入细胞质以建立有效的复制。我们的结果表明，与ASFV相比，痘苗病毒或腺病毒5对胆固醇流出有不同的要求。
