tetano
Editor, Senior Moderator
J Virol. 2015 Jan 28. pii: JVI.02132-14. [Epub ahead of print]
[h=1]PA-X Decreases the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus in Avian Species by Inhibiting Virus replication and Host Response.[/h] Hu J[SUP]1[/SUP], Mo Y[SUP]1[/SUP], Wang X[SUP]1[/SUP], Gu M[SUP]1[/SUP], Hu Z[SUP]1[/SUP], Zhong L[SUP]1[/SUP], Wu Q[SUP]1[/SUP], Hao X[SUP]1[/SUP], Hu S[SUP]1[/SUP], Liu W[SUP]1[/SUP], Liu H[SUP]1[/SUP], Liu X[SUP]1[/SUP], Liu X[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] PA-X is a newly discovered protein that decreases the virulence of 1918 H1N1 virus in a mouse model. However, the role of PA-X in the pathogenesis of highly pathogenic avian influenza virus (HPAIV) H5N1 subtype in avian species is totally unknown. By generating two PA-X-deficient viruses and evaluating their virulence in different animal models, we here showed that PA-X diminishes the virulence of a HPAIV H5N1 strain A/Chicken/Jiangsu/k0402/2010 (CK10) in mice, chickens and ducks. Expression of PA-X dampens the 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, which includes markedly down-regulates genes associated with the inflammatory and cell death response. Correspondingly, decreased cytokine response was recapitulated in multiple organs of chickens and ducks infected with the wild type virus when compared to infect with the PA-X-deficient virus. In addition, the PA-X protein exhibits anti-apoptotic activity in CEF and DEF cells. Thus, our results demonstrated that PA-X acts as a negative virulence regulator and decreases the virulence through 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.
[h=4]IMPORTANCE:[/h] Influenza A virus (IAV) continues to pose a huge threat to global public health. Eight gene segments of the IAV genome encode up to 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 and acts to decrease the virulence of 1918 H1N1 virus in mice through modulating host gene expression. Our study extends these functions of PA-X to HPAIV H5N1 virus. We demonstrated that loss of PA-X expression increases the virulence and virus replication of H5N1 virus in mice and avian species, and alters the host innate immune and cell death response. Our study is the first report delineating the role of the novel PA-X protein in the pathogenesis of H5N1 in avian species and promotes our understanding of HPAIV H5N1 virus.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25631083 [PubMed - as supplied by publisher]
[h=1]PA-X Decreases the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus in Avian Species by Inhibiting Virus replication and Host Response.[/h] Hu J[SUP]1[/SUP], Mo Y[SUP]1[/SUP], Wang X[SUP]1[/SUP], Gu M[SUP]1[/SUP], Hu Z[SUP]1[/SUP], Zhong L[SUP]1[/SUP], Wu Q[SUP]1[/SUP], Hao X[SUP]1[/SUP], Hu S[SUP]1[/SUP], Liu W[SUP]1[/SUP], Liu H[SUP]1[/SUP], Liu X[SUP]1[/SUP], Liu X[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] PA-X is a newly discovered protein that decreases the virulence of 1918 H1N1 virus in a mouse model. However, the role of PA-X in the pathogenesis of highly pathogenic avian influenza virus (HPAIV) H5N1 subtype in avian species is totally unknown. By generating two PA-X-deficient viruses and evaluating their virulence in different animal models, we here showed that PA-X diminishes the virulence of a HPAIV H5N1 strain A/Chicken/Jiangsu/k0402/2010 (CK10) in mice, chickens and ducks. Expression of PA-X dampens the 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, which includes markedly down-regulates genes associated with the inflammatory and cell death response. Correspondingly, decreased cytokine response was recapitulated in multiple organs of chickens and ducks infected with the wild type virus when compared to infect with the PA-X-deficient virus. In addition, the PA-X protein exhibits anti-apoptotic activity in CEF and DEF cells. Thus, our results demonstrated that PA-X acts as a negative virulence regulator and decreases the virulence through 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.
[h=4]IMPORTANCE:[/h] Influenza A virus (IAV) continues to pose a huge threat to global public health. Eight gene segments of the IAV genome encode up to 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 and acts to decrease the virulence of 1918 H1N1 virus in mice through modulating host gene expression. Our study extends these functions of PA-X to HPAIV H5N1 virus. We demonstrated that loss of PA-X expression increases the virulence and virus replication of H5N1 virus in mice and avian species, and alters the host innate immune and cell death response. Our study is the first report delineating the role of the novel PA-X protein in the pathogenesis of H5N1 in avian species and promotes our understanding of HPAIV H5N1 virus.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25631083 [PubMed - as supplied by publisher]