Among mammals, bats are particularly rich in zoonotic viruses, including flaviviruses. Certain bat species can be productively yet asymptomatically infected with viruses that cause overt disease in other species. However, little is known about the antiviral effector repertoire in bats relative to other mammals. Here, we report the black flying fox receptor transporter protein 4 (RTP4) as a potent interferon (IFN)-inducible inhibitor of human pathogens in the Flaviviridae family, including Zika, West Nile, and hepatitis C viruses. Mechanistically, RTP4 associates with the flavivirus replicase, binds viral RNA, and suppresses viral genome amplification. Comparative approaches revealed that RTP4 undergoes positive selection, that a flavivirus can mutate to escape RTP4-imposed restriction, and that diverse mammalian RTP4 orthologs exhibit striking patterns of specificity against distinct Flaviviridae members. Our findings reveal an antiviral mechanism that has likely adapted over 100 million years of mammalian evolution to accommodate unique host-virus genetic conflicts.

在哺乳动物中，蝙蝠尤其富含人畜共患病毒，包括黄病毒。某些蝙蝠物种可以在无症状的情况下高效地感染导致其他物种明显疾病的病毒。然而，与其他哺乳动物相比，蝙蝠的抗病毒效应库知之甚少。在这里，我们报告了黑飞狐受体转运蛋白 4 (RTP4) 作为黄病毒科人类病原体的有效干扰素 (IFN) 诱导抑制剂包括寨卡病毒、西尼罗河病毒和丙型肝炎病毒。从机制上讲，RTP4 与黄病毒复制酶结合，结合病毒 RNA，并抑制病毒基因组扩增。比较方法表明，RTP4 经历正选择，黄病毒可以突变以逃避 RTP4 施加的限制，并且不同的哺乳动物 RTP4 直向同源物对不同的黄病毒科成员表现出惊人的特异性模式。我们的研究结果揭示了一种抗病毒机制，该机制可能已经适应了超过 1 亿年的哺乳动物进化，以适应独特的宿主病毒遗传冲突。