PB2 and NP of North American H5N1 virus drive immune cell replication and systemic infections
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.
Authors
- Richard J. Webby (ORCID: https://orcid.org/0000-0002-4397-7132)
- Dongbin Park (ORCID: https://orcid.org/0000-0001-5289-1034)
- Jaemoo Kim (ORCID: https://orcid.org/0009-0003-4216-8397)
- Mark Anthony B. Casel (ORCID: https://orcid.org/0000-0002-8313-4076)
- Seo-Young Heo
- Rare Rollon (ORCID: https://orcid.org/0000-0002-8428-1713)
- Juryeon Gil (ORCID: https://orcid.org/0000-0002-9415-0688)
- Jae‐Woo Ahn (ORCID: https://orcid.org/0000-0002-2706-5010)
- Seung‐Gyu Jang (ORCID: https://orcid.org/0000-0001-9316-1652)
- Young Ki Choi (ORCID: https://orcid.org/0000-0002-0872-0147)
- Boyeong Jeong (ORCID: https://orcid.org/0009-0008-2541-0328)
- Jeong Ho Choi
- Thomas Fabrizio (ORCID: https://orcid.org/0000-0002-8960-0728)
- Eun-Ha Kim (ORCID: https://orcid.org/0000-0003-1443-3416)
- Hyunjoon Kim (ORCID: https://orcid.org/0000-0002-0207-1190)
- Young‐Il Kim (ORCID: https://orcid.org/0000-0002-0145-7382)
- Se‐Mi Kim (ORCID: https://orcid.org/0000-0001-7932-1381)
- Woohyun Kwon (ORCID: https://orcid.org/0009-0006-9023-0273)
- Suhee Hwang (ORCID: https://orcid.org/0000-0002-1028-1323)
- Mina Yu (ORCID: https://orcid.org/0000-0003-3311-7515)
- Isaac Choi
Institutions
- St. Jude Children's Research Hospital (US)
- Chungbuk National University (KR)
- Institute for Basic Science (KR)
- Korea Basic Science Institute (KR)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1126/sciadv.ady1208
- Citations
- 1
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.35