tetano
Editor, Senior Moderator
Sci Adv
. 2025 Sep 26;11(39):eady1208.
doi: 10.1126/sciadv.ady1208. Epub 2025 Sep 26. PB2 and NP of North American H5N1 virus drive immune cell replication and systemic infections
Young-Il Kim[SUP] 1 [/SUP], Seung-Gyu Jang[SUP] 2 3 [/SUP], Woohyun Kwon[SUP] 1 3 [/SUP], Jaemoo Kim[SUP] 1 [/SUP], Dongbin Park[SUP] 1 [/SUP], Isaac Choi[SUP] 1 [/SUP], Jeong Ho Choi[SUP] 3 [/SUP], Juryeon Gil[SUP] 1 3 [/SUP], Mina Yu[SUP] 1 3 [/SUP], Boyeong Jeong[SUP] 1 [/SUP], Eun-Ha Kim[SUP] 2 [/SUP], Se-Mi Kim[SUP] 1 [/SUP], Hyunjoon Kim[SUP] 1 [/SUP], Jae-Woo Ahn[SUP] 1 [/SUP], Suhee Hwang[SUP] 1 4 [/SUP], Seo-Young Heo[SUP] 1 4 [/SUP], Mark Anthony B Casel[SUP] 1 3 [/SUP], Rare Rollon[SUP] 1 3 [/SUP], Thomas Fabrizio[SUP] 5 [/SUP], Richard J Webby[SUP] 5 [/SUP], Young Ki Choi[SUP] 1 2 3 4 [/SUP]
Affiliations
The 2022 North American outbreak of 2.3.4.4b H5N1 avian influenza virus revealed substantial mammalian adaptation and pathogenicity, yet mechanisms remain unclear. To address this knowledge gap, we investigated the North American H5N1 strain (GA/W22-145E/22), which demonstrated unique immune cell-mediated systemic dissemination, neuroinvasion, and 100% mortality in ferrets, unlike the nonlethal Eurasian strain (KR/W811/21). Genomic and reverse genetics studies identified PB2[SUB]478I[/SUB] and NP[SUB]450N[/SUB] mutations as key determinants of enhanced polymerase activity, immune cell tropism, and pathogenicity. Mutant GA/W22-145E/22 virus carrying PB2[SUB]478V[/SUB]/NP[SUB]450S[/SUB] showed complete survival without systemic dissemination. Furthermore, GA/W22-145E/22 demonstrated robust replication in human peripheral blood mononuclear cells and bovine mammary gland organoids, raising concerns about zoonotic spillover. These findings underscore PB2[SUB]478I[/SUB] and NP[SUB]450N[/SUB] as pivotal markers of pathogenicity, emphasizing the urgent need for enhanced surveillance and targeted interventions.
. 2025 Sep 26;11(39):eady1208.
doi: 10.1126/sciadv.ady1208. Epub 2025 Sep 26. PB2 and NP of North American H5N1 virus drive immune cell replication and systemic infections
Young-Il Kim[SUP] 1 [/SUP], Seung-Gyu Jang[SUP] 2 3 [/SUP], Woohyun Kwon[SUP] 1 3 [/SUP], Jaemoo Kim[SUP] 1 [/SUP], Dongbin Park[SUP] 1 [/SUP], Isaac Choi[SUP] 1 [/SUP], Jeong Ho Choi[SUP] 3 [/SUP], Juryeon Gil[SUP] 1 3 [/SUP], Mina Yu[SUP] 1 3 [/SUP], Boyeong Jeong[SUP] 1 [/SUP], Eun-Ha Kim[SUP] 2 [/SUP], Se-Mi Kim[SUP] 1 [/SUP], Hyunjoon Kim[SUP] 1 [/SUP], Jae-Woo Ahn[SUP] 1 [/SUP], Suhee Hwang[SUP] 1 4 [/SUP], Seo-Young Heo[SUP] 1 4 [/SUP], Mark Anthony B Casel[SUP] 1 3 [/SUP], Rare Rollon[SUP] 1 3 [/SUP], Thomas Fabrizio[SUP] 5 [/SUP], Richard J Webby[SUP] 5 [/SUP], Young Ki Choi[SUP] 1 2 3 4 [/SUP]
Affiliations
- PMID: 41004584
- DOI: 10.1126/sciadv.ady1208
The 2022 North American outbreak of 2.3.4.4b H5N1 avian influenza virus revealed substantial mammalian adaptation and pathogenicity, yet mechanisms remain unclear. To address this knowledge gap, we investigated the North American H5N1 strain (GA/W22-145E/22), which demonstrated unique immune cell-mediated systemic dissemination, neuroinvasion, and 100% mortality in ferrets, unlike the nonlethal Eurasian strain (KR/W811/21). Genomic and reverse genetics studies identified PB2[SUB]478I[/SUB] and NP[SUB]450N[/SUB] mutations as key determinants of enhanced polymerase activity, immune cell tropism, and pathogenicity. Mutant GA/W22-145E/22 virus carrying PB2[SUB]478V[/SUB]/NP[SUB]450S[/SUB] showed complete survival without systemic dissemination. Furthermore, GA/W22-145E/22 demonstrated robust replication in human peripheral blood mononuclear cells and bovine mammary gland organoids, raising concerns about zoonotic spillover. These findings underscore PB2[SUB]478I[/SUB] and NP[SUB]450N[/SUB] as pivotal markers of pathogenicity, emphasizing the urgent need for enhanced surveillance and targeted interventions.