Hu Jiao, Mo Yiqun, Wang Xiaoquan, Gu Min, Hu Zenglei, Zhong Lei, Wu Qiwen, Hao Xiaoli, Hu Shunlin, Liu Wenbo, Liu Huimou, Liu Xiaowen, Liu Xiufan
Animal Infectious Disease Laboratory, School of Veterinary Medicine, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China.
Animal Infectious Disease Laboratory, School of Veterinary Medicine, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China
J Virol. 2015 Apr;89(8):4126-42. doi: 10.1128/JVI.02132-14. Epub 2015 Jan 28.
PA-X is a newly discovered protein that decreases the virulence of the 1918 H1N1 virus in a mouse model. However, the role of PA-X in the pathogenesis of highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype in avian species is totally unknown. By generating two PA-X-deficient viruses and evaluating their virulence in different animal models, we show here that PA-X diminishes the virulence of the HPAIV H5N1 strain A/Chicken/Jiangsu/k0402/2010 (CK10) in mice, chickens, and ducks. Expression of PA-X dampens polymerase activity and virus replication both in vitro and in vivo. Using microarray analysis, we found that PA-X blunts the global host response in chicken lungs, markedly downregulating genes associated with the inflammatory and cell death responses. Correspondingly, a decreased cytokine response was recapitulated in multiple organs of chickens and ducks infected with the wild-type virus relative to those infected with the PA-X-deficient virus. In addition, the PA-X protein exhibits antiapoptotic activity in chicken and duck embryo fibroblasts. Thus, our results demonstrated that PA-X acts as a negative virulence regulator and decreases virulence by inhibiting viral replication and the host innate immune response. Therefore, we here define the role of PA-X in the pathogenicity of H5N1 HPAIV, furthering our understanding of the intricate pathogenesis of influenza A virus.
Influenza A virus (IAV) continues to pose a huge threat to global public health. Eight gene segments of the IAV genome encode as many as 17 proteins, including 8 main viral proteins and 9 accessory proteins. The presence of these accessory proteins may further complicate the pathogenesis of IAV. PA-X is a newly identified protein in segment 3 that acts to decrease the virulence of the 1918 H1N1 virus in mice by modulating host gene expression. Our study extends these functions of PA-X to H5N1 HPAIV. We demonstrated that loss of PA-X expression increases the virulence and replication of an H5N1 virus in mice and avian species and alters the host innate immune and cell death responses. Our report is the first to delineate the role of the novel PA-X protein in the pathogenesis of H5N1 viruses in avian species and promotes our understanding of H5N1 HPAIV.
PA-X是一种新发现的蛋白质，在小鼠模型中可降低1918年H1N1病毒的毒力。然而，PA-X在H5N1亚型高致病性禽流感病毒（HPAIV）在禽类中的发病机制中的作用完全未知。通过构建两种PA-X缺陷型病毒并在不同动物模型中评估它们的毒力，我们在此表明PA-X可降低HPAIV H5N1毒株A/Chicken/Jiangsu/k0402/2010（CK10）在小鼠、鸡和鸭中的毒力。PA-X的表达在体外和体内均会减弱聚合酶活性和病毒复制。通过微阵列分析，我们发现PA-X可抑制鸡肺中的整体宿主反应，显著下调与炎症和细胞死亡反应相关的基因。相应地，与感染PA-X缺陷型病毒的鸡和鸭相比，感染野生型病毒的鸡和鸭的多个器官中的细胞因子反应减弱。此外，PA-X蛋白在鸡和鸭胚成纤维细胞中表现出抗凋亡活性。因此，我们的结果表明PA-X作为一种负性毒力调节因子，通过抑制病毒复制和宿主先天免疫反应来降低毒力。因此，我们在此确定了PA-X在H5N1 HPAIV致病性中的作用，加深了我们对甲型流感病毒复杂发病机制的理解。
甲型流感病毒（IAV）继续对全球公共卫生构成巨大威胁。IAV基因组的8个基因节段编码多达17种蛋白质，包括8种主要病毒蛋白和9种辅助蛋白。这些辅助蛋白的存在可能会使IAV的发病机制更加复杂。PA-X是第3节段中新鉴定的一种蛋白质，通过调节宿主基因表达来降低1918年H1N1病毒在小鼠中的毒力。我们的研究将PA-X的这些功能扩展到H5N1 HPAIV。我们证明，PA-X表达缺失会增加H5N1病毒在小鼠和禽类中的毒力和复制，并改变宿主先天免疫和细胞死亡反应。我们的报告首次阐述了新型PA-X蛋白在H5N1病毒在禽类发病机制中的作用，并促进了我们对H5N1 HPAIV的理解。
