@article{mbs:/content/journal/jgv/10.1099/jgv.0.000232, author = "Gao, Huijie and Xu, Guanlong and Sun, Yipeng and Qi, Lu and Wang, Jinliang and Kong, Weili and Sun, Honglei and Pu, Juan and Chang, Kin-Chow and Liu, Jinhua", title = "PA-X is a virulence factor in avian H9N2 influenza virus", journal= "Journal of General Virology", year = "2015", volume = "96", number = "9", pages = "2587-2594", doi = "https://doi.org/10.1099/jgv.0.000232", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000232", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", abstract = "H9N2 influenza viruses have been circulating worldwide in multiple avian species, and regularly infect pigs and humans. Recently, a novel protein, PA-X, produced from the PA gene by ribosomal frameshifting, was demonstrated to be an antivirulence factor in pandemic 2009 H1N1, highly pathogenic avian H5N1 and 1918 H1N1 viruses. However, a similar role of PA-X in the prevalent H9N2 avian influenza viruses has not been established. In this study, we compared the virulence and cytopathogenicity of H9N2 WT virus and H9N2 PA-X-deficient virus. Loss of PA-X in H9N2 virus reduced apoptosis and had a marginal effect on progeny virus output in human pulmonary adenocarcinoma (A549) cells. Without PA-X, PA was less able to suppress co-expressed GFP in human embryonic kidney 293T cells. Furthermore, absence of PA-X in H9N2 virus attenuated viral pathogenicity in mice, which showed no mortality, reduced progeny virus production, mild-to-normal lung histopathology, and dampened proinflammatory cytokine and chemokine response. Therefore, unlike previously reported H1N1 and H5N1 viruses, we show that PA-X protein in H9N2 virus is a pro-virulence factor in facilitating viral pathogenicity and that the pro- or antivirulence role of PA-X in influenza viruses is virus strain-dependent.", }