title: PA-X decreases the pathogenicity of highly pathogenic H5N1 influenza A virus in avian species by inhibiting virus replication and host response.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors: 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.
authors: Jiao
authors: J
authors: Hu
authors: 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.
authors: Yiqun
authors: Y
authors: Mo
authors: 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.
authors: Xiaoquan
authors: X
authors: Wang
authors: 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.
authors: Min
authors: M
authors: Gu
authors: 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.
authors: Zenglei
authors: Z
authors: Hu
authors: 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.
authors: Lei
authors: L
authors: Zhong
authors: 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.
authors: Qiwen
authors: Q
authors: Wu
authors: 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.
authors: Xiaoli
authors: X
authors: Hao
authors: 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.
authors: Shunlin
authors: S
authors: Hu
authors: 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.
authors: Wenbo
authors: W
authors: Liu
authors: 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.
authors: Huimou
authors: H
authors: Liu
authors: 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.
authors: Xiaowen
authors: X
authors: Liu
authors: 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 xfliu@yzu.edu.cn.
authors: Xiufan
authors: X
authors: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002458:Cell Fractionation; D002460:Cell Line; D002645:Chickens; D004285:Dogs; D004372:Ducks; D005455:Fluorescent Antibody Technique; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000378:metabolism* / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000378:metabolism / Q000821:virology*; D008156:Luciferases; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics*
chemical_list: C573926:PA-X protein, influenza A virus; D012097:Repressor Proteins; D017361:Viral Nonstructural Proteins; D008156:Luciferases
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