Zhang Xin, Tao Yingying, Wu Li, Shu Jianhong, He Yulong, Feng Huapeng
Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
Front Cell Infect Microbiol. 2025 Mar 14;15:1560250. doi: 10.3389/fcimb.2025.1560250. eCollection 2025.
In recent years, the influenza viruses have posed an increasingly severe threat to public health. It is essential to analyze the virulence and pathogenesis of influenza viruses to prevent and control them, as well as create antiviral drugs. Previous studies have revealed that influenza virus segment 3 codes for not only the PA protein but also a novel protein, PA-X. PA protein is one subunit of the polymerase of influenza viruses and plays a critical role in its life cycle. PA presented endonuclease activity, the transcription and replication of the viral genome, viral virulence, protein degradation, and host immune response by interacting with viral proteins, including PB2, PB1, and host factors, including ANP32A, CHD6, HAX1, hCLE, HDAC6, MCM complex. PA mutations were involved in the viral replication, pathogenicity, and transmission of influenza viruses in poultry, mammals, and humans. PA-X is an open reading frame generated by +1 ribosomal code shift at the N-terminal amino acids of segment 3 and possesses the shutoff activity of host gene expression, regulating the host immune response, viral virulence and transmission. Therefore, PA is one ideal target for the development of antiviral drugs against influenza viruses. Baloxavir marboxil (BXM) and Favipiravir are two very effective anti-influenza virus drugs targeting the PA endonuclease domain of influenza A viruses. In this review, we summarized the structures, viral replication, virulent determinants and transmission, host factors, innate immunity, and antiviral drugs involved in PA and PA-X. The information is of great value for underlying the mechanism of viral replication and developing novel effective strategies to prevent and control influenza infection and the pandemic.
近年来，流感病毒对公众健康构成的威胁日益严峻。分析流感病毒的毒力和发病机制对于预防和控制流感病毒以及研发抗病毒药物至关重要。先前的研究表明，流感病毒第3节段不仅编码PA蛋白，还编码一种新型蛋白PA-X。PA蛋白是流感病毒聚合酶的一个亚基，在其生命周期中起关键作用。PA通过与包括PB2、PB1在内的病毒蛋白以及包括ANP32A、CHD6、HAX1、hCLE、HDAC6、MCM复合物在内的宿主因子相互作用，呈现出核酸内切酶活性、病毒基因组的转录和复制、病毒毒力、蛋白质降解以及宿主免疫反应。PA突变参与了流感病毒在家禽、哺乳动物和人类中的复制、致病性和传播。PA-X是由第3节段N端氨基酸处的+1核糖体密码移码产生的开放阅读框，具有宿主基因表达的关闭活性，调节宿主免疫反应、病毒毒力和传播。因此，PA是开发抗流感病毒药物的理想靶点之一。巴洛沙韦酯（BXM）和法匹拉韦是两种非常有效的抗甲型流感病毒药物，靶向流感病毒的PA核酸内切酶结构域。在本综述中，我们总结了与PA和PA-X相关的结构、病毒复制、毒力决定因素和传播、宿主因子、固有免疫以及抗病毒药物。这些信息对于深入了解病毒复制机制以及制定预防和控制流感感染及大流行的新型有效策略具有重要价值。
