PA-X is an avian virulence factor in H9N2 avian influenza virus

Abstract

Influenza A viruses encode several accessory proteins that have host- and strain-specific effects on virulence and replication. The accessory protein PA-X is expressed due to a ribosomal frameshift during translation of the PA gene. Depending on the particular combination of virus strain and host species, PA-X has been described as either acting to reduce or increase virulence and/or virus replication. In this study, we set out to investigate the role PA-X plays in H9N2 avian influenza viruses, focusing on the natural avian host, chickens. We found that the G1 lineage A/chicken/Pakistan/UDL-01/2008 (H9N2) PA-X induced robust host shutoff in both mammalian and avian cells and increased virus replication in mammalian, but not avian cells. We further showed that PA-X affected embryonic lethality in ovo and led to more rapid viral shedding and widespread organ dissemination in vivo in chickens. Overall, we conclude PA-X may act as a virulence factor for H9N2 viruses in chickens, allowing faster replication and wider organ tropism.

PA‐X protein assists H9N2 subtype avian influenza virus in escaping immune response of mucosal dendritic cells

“…Our results suggested that PA-X protein of H9N2 subtype AIVs was a virulence factor in facilitating viral pathogenicity which was consistence with the previous studies (Clements et al, 2021;Gao et al, 2015). For non-immune cells, PA-X protein enhanced the replication level of H9N2 subtype AIVs on MDCK cells, which probably due to the selectivity of PA-X host shut-off activity.…”

“…Consistently, another independent study also found that PA-X protein of H9N2 subtype AIVs enhanced virus replication in produced mammalian cells, increased the pathogenicity in chicken embryos and caused more rapid viral shedding and widespread dissemination in birds (Clements et al, 2021).…”

“…The nasal cavity is a gateway for invasion and shedding of H9N2 subtype AIVs (Clements et al, 2021). When the virus invades, mucosal dendritic cells (DCs), as sentinels, can be quickly recruited under submucosa to subsequently initiate innate immune responses, and increase the expression of the chemokine receptor 7 (CCR7) to ensure that they can migrate from the infection site into the secondary lymphoid tissue to further induce differentiation of cells by presenting antigen to naive T cells (Lee et al, 2015;Qin et al, 2015a;Qin et al, 2015b).…”

PA-X protein of H9N2 subtype avian influenza virus suppresses the innate immunity of chicken bone marrow-derived dendritic cells

“…Therefore, to achieve an in-depth understanding of the influence on host immune cells, we successfully established an induction culture system of chBM-DCs in vitro, which provided a tool for studying the interconnection between avian pathogens and host immune responses. Some studies showed PA-X protein acts as a virulence factor for H9N2 subtype AIVs ( Gao et al., 2015 ; Clements et al., 2021 ). Moreover, PA-X protein selectively only to degrade the host's RNA through its endonuclease activity, but not the virus itself ( Hu et al., 2015 ; Nogales et al., 2017 ; Gaucherand, et al., 2019 ; Rigby et al., 2019 ).…”

“…PA-X of H5N1 subtype AIVs is a negative virulence regulator that can reduce virulence by inhibiting viral replication and host innate immune responses ( Hu et al., 2015 ). In contrary, PA-X protein of H9N2 subtype AIVs, as a virulence factor, can improve the pathogenicity in mammals by enhancing virus replication, cell apoptosis, and lung injury ( Gao et al., 2015 ), and affect the embryos lethality and lead to more rapid shedding and visceral tropism in birds ( Clements et al., 2021 ).…”