tetano
Editor, Senior Moderator
Vet Microbiol
. 2026 May 21:318:111074.
doi: 10.1016/j.vetmic.2026.111074. Online ahead of print.
NS1-A53D enhances HA stability to coordinate viral entry with vRNP export and replication during adaptation of H1N1 canine influenza virus
Min Zhu[SUP] 1 [/SUP], Rang Wang[SUP] 1 [/SUP], Xiaolong Li[SUP] 1 [/SUP], Yefan Zhou[SUP] 1 [/SUP], Linying Peng[SUP] 1 [/SUP], Pingping Wang[SUP] 1 [/SUP], Huabo Zhou[SUP] 2 [/SUP], Jianni Huang[SUP] 3 [/SUP], Yifeng Qin[SUP] 3 [/SUP], Kang Ouyang[SUP] 3 [/SUP], Yeshi Yin[SUP] 3 [/SUP], Zuzhang Wei[SUP] 3 [/SUP], Weijian Huang[SUP] 3 [/SUP], Ying Chen[SUP] 4 [/SUP]
Affiliations
Eurasian avian-like H1N1 influenza A viruses that have reassorted with the 2009 pandemic H1N1 virus pose a potential public health threat. We previously reported that synergistic mutations in HA and NS genes enhanced the virulence of a mouse-adapted EA H1N1 canine influenza virus (CIV), yet the underlying mechanisms remained unclear. Here, we demonstrate that the adaptive mutations NS1-A53D and NEP-R42K synergistically promote viral replication by enhancing viral ribonucleoprotein (vRNP) nuclear export, while NEP-R42K alone boosts polymerase activity. Critically, we uncover a novel synergy between HA mutations (N198D and A227E) and NS1-A53D, but not NEP-R42K, in facilitating early viral entry, including attachment and internalization. Mechanistically, NS1-A53D significantly enhances HA protein stability without altering receptor binding specificity, thereby compensating for the intrinsic antagonism between the two HA mutations that impairs receptor binding affinity. These findings reveal that HA and NS genes cooperate through distinct but complementary mechanisms: NS1-A53D stabilizes HA to promote entry, while NS1-A53D and NEP-R42K collaboratively enhance vRNP export, collectively driving mammalian adaptation and pathogenicity.
Keywords: HA stability; Influenza A virus; NS1-A53D mutation; Synergic effect; VRNP nuclear export
. 2026 May 21:318:111074.
doi: 10.1016/j.vetmic.2026.111074. Online ahead of print.
NS1-A53D enhances HA stability to coordinate viral entry with vRNP export and replication during adaptation of H1N1 canine influenza virus
Min Zhu[SUP] 1 [/SUP], Rang Wang[SUP] 1 [/SUP], Xiaolong Li[SUP] 1 [/SUP], Yefan Zhou[SUP] 1 [/SUP], Linying Peng[SUP] 1 [/SUP], Pingping Wang[SUP] 1 [/SUP], Huabo Zhou[SUP] 2 [/SUP], Jianni Huang[SUP] 3 [/SUP], Yifeng Qin[SUP] 3 [/SUP], Kang Ouyang[SUP] 3 [/SUP], Yeshi Yin[SUP] 3 [/SUP], Zuzhang Wei[SUP] 3 [/SUP], Weijian Huang[SUP] 3 [/SUP], Ying Chen[SUP] 4 [/SUP]
Affiliations
- PMID: 42176433
- DOI: 10.1016/j.vetmic.2026.111074
Eurasian avian-like H1N1 influenza A viruses that have reassorted with the 2009 pandemic H1N1 virus pose a potential public health threat. We previously reported that synergistic mutations in HA and NS genes enhanced the virulence of a mouse-adapted EA H1N1 canine influenza virus (CIV), yet the underlying mechanisms remained unclear. Here, we demonstrate that the adaptive mutations NS1-A53D and NEP-R42K synergistically promote viral replication by enhancing viral ribonucleoprotein (vRNP) nuclear export, while NEP-R42K alone boosts polymerase activity. Critically, we uncover a novel synergy between HA mutations (N198D and A227E) and NS1-A53D, but not NEP-R42K, in facilitating early viral entry, including attachment and internalization. Mechanistically, NS1-A53D significantly enhances HA protein stability without altering receptor binding specificity, thereby compensating for the intrinsic antagonism between the two HA mutations that impairs receptor binding affinity. These findings reveal that HA and NS genes cooperate through distinct but complementary mechanisms: NS1-A53D stabilizes HA to promote entry, while NS1-A53D and NEP-R42K collaboratively enhance vRNP export, collectively driving mammalian adaptation and pathogenicity.
Keywords: HA stability; Influenza A virus; NS1-A53D mutation; Synergic effect; VRNP nuclear export