TY - JOUR
T1 - The potential of H5N1 viruses to adapt to bovine cells varies throughout evolution
AU - Turnbull, Matthew L.
AU - Zakaria, Mohammad Khalid
AU - Upfold, Nicole S.
AU - Bakshi, Siddharth
AU - Magill, Callum
AU - Das, Udeet Ranjan
AU - Clarke, Andrew T.
AU - Mojsiejczuk, Laura
AU - Herder, Vanessa
AU - Dee, Kieran
AU - Liu, Nancy
AU - Folwarczna, Monika
AU - Ilia, Georgios
AU - Furnon, Wilhelm
AU - Schultz, Verena
AU - Chen, Hanting
AU - Devlin, Ryan
AU - McCowan, Jack
AU - Young, Alex L.
AU - Po, Wai Wai
AU - Smollett, Katherine
AU - Yaseen, Muhammad Ahsan
AU - Ross, Rebecca
AU - Bhide, Avanti
AU - van Kekem, Bianca
AU - Fouchier, Ron A.M.
AU - da Silva Filipe, Ana
AU - Iqbal, Munir
AU - Roberts, Ed
AU - Hughes, Joseph
AU - Werling, Dirk
AU - Murcia, Pablo R.
AU - Palmarini, Massimo
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12/15
Y1 - 2025/12/15
N2 - Avian influenza H5N1 clade 2.3.4.4b viruses caused a global panzootic and, unexpectedly, widespread outbreaks in dairy cattle, therefore representing a pandemic threat. To inform control strategies, it is critical to determine whether the potential to adapt to bovine cells is a general feature of H5N1 viruses, is specific to viruses of clade 2.3.4.4b, or narrowly restricted to some genotypes within this clade. Using a large panel of recombinant viruses representing >60 years of H5N1 history and other IAVs for comparison, we demonstrate replicative fitness in bovine cells is: (i) highly variable across 2.3.4.4b genotypes, (ii) limited in viruses predating the global expansion of this clade, (iii) determined by the internal gene cassette, and (iv) not restricted to udder epithelial cells. Mutations in the PB2 polymerase subunit emerge as key determinants of adaptation, although their phenotypic effects are context dependent. Bovine B3.13 and some avian genotypes exhibit enhanced modulation of bovine interferon-induced antiviral responses, determined by at least PB2, nucleoprotein, and the non-structural protein NS1. Our results highlight the polygenic nature of IAV host range, and reveal that the replication fitness in bovine cells, and likely their potential to adapt to cattle, varies greatly during the evolutionary trajectory of H5N1 viruses.
AB - Avian influenza H5N1 clade 2.3.4.4b viruses caused a global panzootic and, unexpectedly, widespread outbreaks in dairy cattle, therefore representing a pandemic threat. To inform control strategies, it is critical to determine whether the potential to adapt to bovine cells is a general feature of H5N1 viruses, is specific to viruses of clade 2.3.4.4b, or narrowly restricted to some genotypes within this clade. Using a large panel of recombinant viruses representing >60 years of H5N1 history and other IAVs for comparison, we demonstrate replicative fitness in bovine cells is: (i) highly variable across 2.3.4.4b genotypes, (ii) limited in viruses predating the global expansion of this clade, (iii) determined by the internal gene cassette, and (iv) not restricted to udder epithelial cells. Mutations in the PB2 polymerase subunit emerge as key determinants of adaptation, although their phenotypic effects are context dependent. Bovine B3.13 and some avian genotypes exhibit enhanced modulation of bovine interferon-induced antiviral responses, determined by at least PB2, nucleoprotein, and the non-structural protein NS1. Our results highlight the polygenic nature of IAV host range, and reveal that the replication fitness in bovine cells, and likely their potential to adapt to cattle, varies greatly during the evolutionary trajectory of H5N1 viruses.
UR - https://www.scopus.com/pages/publications/105024792036
U2 - 10.1038/s41467-025-67234-1
DO - 10.1038/s41467-025-67234-1
M3 - Article
C2 - 41398153
AN - SCOPUS:105024792036
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 11042
ER -