Filovirus Laboratory, INSERM U758, Human Virology Department, Université de Lyon, Ecole Normale Supérieure de Lyon, Lyon, France.
J Infect Dis. 2011 Nov;204 Suppl 3:S1011-20. doi: 10.1093/infdis/jir338.
In sharp contrast to human and nonhuman primates, guinea pigs and some other mammals resist Ebola virus (EBOV) replication and do not develop illness upon virus inoculation. However, serial passaging of EBOV in guinea pigs results in a selection of variants with high pathogenicity. In this report, using a reverse genetics approach, we demonstrate that this dramatic increase in EBOV pathogenicity is associated with amino acid substitutions in the structural protein VP24. We show that although replication of recombinant EBOV carrying wild-type VP24 is impaired in primary peritoneal guinea pig macrophages and in the liver of infected animals, the substitutions in VP24 allow EBOV to replicate in guinea pig macrophages and spread in the liver of infected animals. Furthermore, we demonstrate that both VP24/wild type and the guinea pig-adapted VP24/8mc are similar in their ability to block expression of interferon-induced host genes, suggesting that the increase in EBOV virulence for guinea pigs is not associated with VP24 interferon antagonist function. This study sheds light on the mechanism of resistance to EBOV infection and highlights the critical role of VP24 in EBOV pathogenesis.
与人类和非人类灵长类动物形成鲜明对比的是，豚鼠和其他一些哺乳动物能够抵抗埃博拉病毒（EBOV）的复制，并且在接种病毒后不会发病。然而，在豚鼠中对 EBOV 进行连续传代会导致选择出具有高致病性的变体。在本报告中，我们使用反向遗传学方法证明，EBOV 致病性的这种显著增加与结构蛋白 VP24 中的氨基酸取代有关。我们表明，尽管携带野生型 VP24 的重组 EBOV 的复制在原代豚鼠腹膜巨噬细胞和感染动物的肝脏中受到损害，但 VP24 中的取代允许 EBOV 在豚鼠巨噬细胞中复制，并在感染动物的肝脏中传播。此外，我们证明 VP24/野生型和适应豚鼠的 VP24/8mc 在阻断干扰素诱导的宿主基因表达的能力方面相似，这表明 EBOV 对豚鼠的毒力增加与 VP24 干扰素拮抗剂功能无关。本研究揭示了对 EBOV 感染的抵抗机制，并强调了 VP24 在 EBOV 发病机制中的关键作用。
