Caridi Flavia, Vázquez-Calvo Angela, Sobrino Francisco, Martín-Acebes Miguel A
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain
J Virol. 2015 May;89(10):5633-42. doi: 10.1128/JVI.03358-14. Epub 2015 Mar 11.
The picornavirus foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects important livestock species. The FMDV capsid is highly acid labile, and viral particles lose infectivity due to their disassembly at pH values slightly below neutrality. This acid sensitivity is related to the mechanism of viral uncoating and genome penetration from endosomes. In this study, we have analyzed the molecular basis of FMDV acid-induced disassembly by isolating and characterizing a panel of novel FMDV mutants differing in acid sensitivity. Amino acid replacements altering virion stability were preferentially distributed in two different regions of the capsid: the N terminus of VP1 and the pentameric interface. Even more, the acid labile phenotype induced by a mutation located at the pentameric interface in VP3 could be compensated by introduction of an amino acid substitution in the N terminus of VP1. These results indicate that the acid sensitivity of FMDV can be considered a multifactorial trait and that virion stability is the fine-tuned product of the interaction between residues from different capsid proteins, in particular those located within the N terminus of VP1 or close to the pentameric interface.
The viral capsid protects the viral genome from environmental factors and contributes to virus dissemination and infection. Thus, understanding of the molecular mechanisms that modulate capsid stability is of interest for the basic knowledge of the biology of viruses and as a tool to improve the stability of conventional vaccines based on inactivated virions or empty capsids. Using foot-and-mouth disease virus (FMDV), which displays a capsid with extreme acid sensitivity, we have performed a genetic study to identify the molecular determinants involved in capsid stability. A panel of FMDV mutants with differential sensitivity to acidic pH was generated and characterized, and the results showed that two different regions of FMDV capsid contribute to modulating viral particle stability. These results provide new insights into the molecular mechanisms of acid-mediated FMDV uncoating.
小RNA病毒科的口蹄疫病毒（FMDV）是一种影响重要家畜物种的高度传染性疾病的病原体。FMDV衣壳对酸高度不稳定，由于病毒颗粒在略低于中性的pH值下解体，其失去感染性。这种酸敏感性与病毒从内体中脱壳和基因组渗透的机制有关。在本研究中，我们通过分离和表征一组在酸敏感性方面不同的新型FMDV突变体，分析了FMDV酸诱导解体的分子基础。改变病毒体稳定性的氨基酸替换优先分布在衣壳的两个不同区域：VP1的N末端和五聚体界面。更重要的是，位于VP3五聚体界面的突变诱导的酸不稳定表型可以通过在VP1的N末端引入氨基酸替换来补偿。这些结果表明，FMDV的酸敏感性可被视为一种多因素性状，病毒体稳定性是不同衣壳蛋白残基之间相互作用的精细调节产物，特别是位于VP1 N末端或靠近五聚体界面的残基。
病毒衣壳保护病毒基因组免受环境因素影响，并有助于病毒传播和感染。因此，了解调节衣壳稳定性的分子机制对于病毒生物学的基础知识以及作为提高基于灭活病毒体或空衣壳的传统疫苗稳定性的工具都具有重要意义。利用具有极端酸敏感性衣壳的口蹄疫病毒（FMDV），我们进行了一项遗传学研究，以确定参与衣壳稳定性的分子决定因素。生成并表征了一组对酸性pH具有不同敏感性的FMDV突变体，结果表明FMDV衣壳的两个不同区域有助于调节病毒颗粒的稳定性。这些结果为酸介导的FMDV脱壳分子机制提供了新的见解。
