Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species and avian strains of IAV replicate poorly in most mammalian hosts. Importantly, IAV polymerases from avian strains function poorly in mammalian cells but host adaptive mutations can restore activity. The 2009 pandemic H1N1 (H1N1pdm09) virus acquired multiple mutations in the PA gene that activated polymerase activity in mammalian cells, even in the absence of previously identified host adaptive mutations in other polymerase genes. These mutations in PA localize within different regions of the protein suggesting multiple mechanisms exist to activate polymerase activity. Additionally, an immunomodulatory protein, PA-X, is expressed from the PA gene segment. PA-X expression is conserved amongst many IAV strains but activity varies between viruses specific for different hosts, suggesting that PA-X also plays a role in host adaptation. Here, we review the role of PA in the emergence of currently circulating H1N1pdm09 viruses and the most recent studies of host adaptive mutations in the PA gene that modulate polymerase activity and PA-X function.

中文翻译：

---

甲型流感病毒 PA 基因片段在大流行病毒出现中的关键作用。

甲型流感病毒 (IAV) 是一种重要的人类病原体，可引起季节性流行病和偶尔的大流行病。鸟类水禽是 IAV 的天然宿主，但可以作为宿主的物种范围很广。大多数 IAV 菌株适应一种宿主物种，而 IAV 的禽类菌株在大多数哺乳动物宿主中的复制能力较差。重要的是，来自禽类的 IAV 聚合酶在哺乳动物细胞中的功能很差，但宿主适应性突变可以恢复活性。2009 年大流行的 H1N1 (H1N1pdm09) 病毒在 PA 基因中获得了多个突变，激活了哺乳动物细胞中的聚合酶活性，即使在先前确定的其他聚合酶基因中没有宿主适应性突变的情况下也是如此。PA 中的这些突变位于蛋白质的不同区域，表明存在多种激活聚合酶活性的机制。此外，免疫调节蛋白 PA-X 从 PA 基因片段中表达出来。PA-X 表达在许多 IAV 毒株中是保守的，但活性因针对不同宿主的病毒而异，这表明 PA-X 在宿主适应中也发挥作用。在这里，我们回顾了 PA 在当前流行的 H1N1pdm09 病毒出现中的作用，以及对 PA 基因中调节聚合酶活性和 PA-X 功能的宿主适应性突变的最新研究。