tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2026 Dec;15(1):2695530.
doi: 10.1080/22221751.2026.2695530. Epub 2026 Jul 8.
Emerged N193S mutation of PA-X protein disabled the immunity of mucosal dendritic cells for regulating virulence of clade 2.3.4.4b H5 subtype virus
Xinyu Miao[SUP] 1 2 [/SUP], Xing Xu[SUP] 1 [/SUP], Yixuan Han[SUP] 1 [/SUP], Yiling Wang[SUP] 1 [/SUP], Wenqing Wang[SUP] 1 [/SUP], Jinyuan Wang[SUP] 1 [/SUP], Yuncong Yin[SUP] 1 [/SUP], Sujuan Chen[SUP] 1 [/SUP], Daxin Peng[SUP] 1 2 3 4 5 6 [/SUP], Tao Qin[SUP] 1 2 3 4 5 6 [/SUP]
Affiliations
In recent years, H5 subtype highly pathogenic avian influenza viruses (HPAIVs), especially clade 2.3.4.4b, have posed a global threat to poultry, cattle, and public health. Bioinformatics analysis of H5 subtype AIVs from 2000 to 2023 revealed a progressive increase in the PA-X N193S mutation, which became predominant in both avian and mammalian isolates of clade 2.3.4.4b. Using reverse genetics, we generated viruses with PA-X 193N (rWT) and 193S (rWT-N193S). The PA-X N193S mutation significantly inhibited viral polymerase activity while enhancing host shutoff. In vitro and vivo, rWT-N193S showed attenuated replication in avian and mammalian cells, reduced pathogenicity in mice, and suppressed cytokine storms. However, it enhanced uptake by dendritic cells (DCs), impairing DC maturation, activation, cytokine secretion, and CD4[SUP]+[/SUP] T cell proliferation. In murine nasal mucosal experiments, the PA-X N193S mutation reduced CCL5 expression, altered DC recruitment, and suppressed IL-17/MAPK signalling. These findings reveal a viral trade-off: the mutation attenuates epithelial replication and immunopathology but enhances DC uptake and disables mucosal immune functions, a strategy that likely contributed to the global predominance of PA-X N193S mutation in epidemic H5 subtype viruses.
Keywords: Avian Influenza virus; IL-17/MAPK signalling pathway; PA-X N193S mutation; dendritic cells; pathogenicity.
. 2026 Dec;15(1):2695530.
doi: 10.1080/22221751.2026.2695530. Epub 2026 Jul 8.
Emerged N193S mutation of PA-X protein disabled the immunity of mucosal dendritic cells for regulating virulence of clade 2.3.4.4b H5 subtype virus
Xinyu Miao[SUP] 1 2 [/SUP], Xing Xu[SUP] 1 [/SUP], Yixuan Han[SUP] 1 [/SUP], Yiling Wang[SUP] 1 [/SUP], Wenqing Wang[SUP] 1 [/SUP], Jinyuan Wang[SUP] 1 [/SUP], Yuncong Yin[SUP] 1 [/SUP], Sujuan Chen[SUP] 1 [/SUP], Daxin Peng[SUP] 1 2 3 4 5 6 [/SUP], Tao Qin[SUP] 1 2 3 4 5 6 [/SUP]
Affiliations
- PMID: 42419306
- DOI: 10.1080/22221751.2026.2695530
In recent years, H5 subtype highly pathogenic avian influenza viruses (HPAIVs), especially clade 2.3.4.4b, have posed a global threat to poultry, cattle, and public health. Bioinformatics analysis of H5 subtype AIVs from 2000 to 2023 revealed a progressive increase in the PA-X N193S mutation, which became predominant in both avian and mammalian isolates of clade 2.3.4.4b. Using reverse genetics, we generated viruses with PA-X 193N (rWT) and 193S (rWT-N193S). The PA-X N193S mutation significantly inhibited viral polymerase activity while enhancing host shutoff. In vitro and vivo, rWT-N193S showed attenuated replication in avian and mammalian cells, reduced pathogenicity in mice, and suppressed cytokine storms. However, it enhanced uptake by dendritic cells (DCs), impairing DC maturation, activation, cytokine secretion, and CD4[SUP]+[/SUP] T cell proliferation. In murine nasal mucosal experiments, the PA-X N193S mutation reduced CCL5 expression, altered DC recruitment, and suppressed IL-17/MAPK signalling. These findings reveal a viral trade-off: the mutation attenuates epithelial replication and immunopathology but enhances DC uptake and disables mucosal immune functions, a strategy that likely contributed to the global predominance of PA-X N193S mutation in epidemic H5 subtype viruses.
Keywords: Avian Influenza virus; IL-17/MAPK signalling pathway; PA-X N193S mutation; dendritic cells; pathogenicity.