BTN3A3 evasion promotes the zoonotic potential of influenza A viruses
BTN3A3 evasion promotes the zoonotic potential of influenza A viruses
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DOI：
10.1038/s41586-023-06261-8
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发表时间：
2023-06-28
期刊：
影响因子：
64.8
通讯作者：
Palmarini, Massimo
中科院分区：
文献类型：
--
作者：
Pinto, Rute Maria;Bakshi, Siddharth;Palmarini, Massimo
禽流感病毒(IAV)对人类的溢出事件可能是未来大流行的第一步(1)。已经确定了几个限制禽类IAV在哺乳动物中传播和复制的因素。在预测哪些病毒谱系更有可能跨越物种障碍并导致人类疾病方面，我们的理解存在几个差距(1)。在这里，我们确定人BTN3A3(丁亲素亚家族3成员A3)(2)是一种有效的禽类IAV抑制物，但不是人IAV的抑制物。我们确定BTN3A3在人类呼吸道中表达，其抗病毒活性在灵长类动物中进化。我们表明，BTN3A3限制主要通过抑制禽类IAV RNA复制在病毒生命周期的早期阶段发挥作用。我们确定病毒核蛋白(NP)中的313残基是BTN3A3敏感性(禽类病毒中为313F或罕见的313L)或逃避(人类病毒中为313Y或313V)的遗传决定因素。然而，传播到人类体内的禽流感病毒血清型，如H7和H9，也绕过了BTN3A3限制。在这些情况下，BTN3A3的逃避是由于NP残基52中与NP结构3中的残基313相邻的替换(N、H或Q)所致。因此，对BTN3A3的敏感性或抗药性是禽流感病毒人畜共患病潜力风险评估中需要考虑的另一个因素。
Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic(1). Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans(1). Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)(2) as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.