Zoladek Jim, El Kazzi Priscila, Caval Vincent, Vivet-Boudou Valérie, Cannac Marion, Davies Emma L, Rossi Soléna, Bribes Inès, Rouilly Lucile, Simonin Yannick, Jouvenet Nolwenn, Decroly Etienne, Paillart Jean-Christophe, Wilson Sam J, Nisole Sébastien
Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR 9004, Montpellier, France.
Architecture et Fonction des Macromolécules Biologiques (AFMB), Aix Marseille Université, CNRS UMR 7257, Marseille, France.
Nat Commun. 2024 Oct 2;15(1):8528. doi: 10.1038/s41467-024-52870-w.
Usutu virus (USUV) and West Nile virus (WNV) are two closely related emerging mosquito-borne flaviviruses. Their natural hosts are wild birds, but they can also cause severe neurological disorders in humans. Both viruses are efficiently suppressed by type I interferon (IFN), which interferes with viral replication, dissemination, pathogenesis and transmission. Here, we show that the replication of USUV and WNV are inhibited through a common set of IFN-induced genes (ISGs), with the notable exception of ISG20, which USUV is resistant to. Strikingly, USUV was the only virus among all the other tested mosquito-borne flaviviruses that demonstrated resistance to the 3'-5' exonuclease activity of ISG20. Our findings highlight that the intrinsic resistance of the USUV genome, irrespective of the presence of cellular or viral proteins or protective post-transcriptional modifications, relies on a unique sequence present in its 3' untranslated region. Importantly, this genomic region alone can confer ISG20 resistance to a susceptible flavivirus, without compromising its infectivity, suggesting that it could be acquired by other flaviviruses. This study provides new insights into the strategy employed by emerging flaviviruses to overcome host defense mechanisms.
乌苏图病毒（USUV）和西尼罗河病毒（WNV）是两种密切相关的、新出现的蚊媒黄病毒。它们的天然宿主是野生鸟类，但也可导致人类出现严重的神经紊乱。这两种病毒都能被I型干扰素（IFN）有效抑制，I型干扰素可干扰病毒的复制、传播、发病机制及传播。在此，我们表明，USUV和WNV的复制通过一组共同的干扰素诱导基因（ISGs）受到抑制，但ISG20是个显著的例外，USUV对其具有抗性。引人注目的是，在所有其他测试的蚊媒黄病毒中，USUV是唯一对ISG20的3'-5'核酸外切酶活性具有抗性的病毒。我们的研究结果突出表明，无论是否存在细胞或病毒蛋白或保护性转录后修饰，USUV基因组的内在抗性都依赖于其3'非翻译区中存在的一个独特序列。重要的是，仅这一基因组区域就能赋予对ISG20敏感的黄病毒抗性，而不影响其感染性，这表明其他黄病毒可能会获得该区域。这项研究为新出现的黄病毒克服宿主防御机制所采用的策略提供了新的见解。
