Polymerase mutations underlie early adaptation of H5N1 influenza virus to dairy cattle and other mammals
Year: 2026
Type: article
Abstract: In 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA resulting in spillbacks into poultry, wild birds and other mammals including humans. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells and tissues, as well as cells of other mammals including humans. We find evidence of several mammalian adaptations in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor for viral genome replication. We show that this mutation adapts the polymerase to better interact with bovine ANP32 proteins, particularly ANP32A, and thereby enhances virus replication in bovine mammary systems and primary human airway cultures. We show that ongoing evolution in the PB2 gene, including E627K and a convergently arising D740N substitution, further increase polymerase activity and virus replication in a range of mammalian cells. Thus, circulation of H5N1 in dairy cattle allows virus adaption improving replicative ability in cattle and poses a continued risk of zoonotic spillover.
Source: Nature Communications
Authors: Vidhi Dholakia, Jessica L. Quantrill, Samuel A. S. Richardson, Nunticha Pankaew, Maryn D. Brown, Jiayun Yang, Fernando Capelastegui, Tereza Masonou, Katie-Marie Case, Jila Ajeian, Maximillian N. J. Woodall, Callum Magill, Graham Freimanis, Amy McCarron, Ecco Staller, Carol M. Sheppard, Ian H. Brown, Pablo R. Murcia, Claire M. Smith, Munir Iqbal, Paul Digard, Wendy S. Barclay, Rute M. Pinto, Thomas P. Peacock, Daniel H. Goldhill
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Department for Environment, Food and Rural Affairs, UK Government, Royal Society, Institut National de la Recherche Agronomique, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council, Animal Health and Veterinary Laboratories Agency
Awards: BBSRC National Bioscience Research Infrastructure: Low Containment Services and Science Platforms, G1294961325, G1789886538, FLU-Trailmap: Transmission and risk of avian influenza: learning more to advance preparedness, G2219541475, G2540756387, YY-EEID US-UK The evolutionary ecology of pathogen emergence via cross-species transmission in the avian-equine influenza system, G278692818, G2788718956, G2884597935, G3034558885, G3537394621, [YY-EEID US-UK XXXX] Predictive phylogenetics for evolutionary and transmission dynamics of newly emerging avian influenza viruses, BBSRC National Bioscience Research Infrastructure: High Containment Services and Science Platforms, G4144779262, G4310914157, G4403430204, Understanding animal health threats from emerging H5 high pathogenicity avian influenza viruses, G4736519091, Mechanistic and Pathway Analysis of Animal Influenza Virus cross-species transmission by constructing genotype and phenotype networks, G4969057763, G5010259280, G5057680655, Flu: TrailMap-One Health, G6312107230, Prevention & Control of Infectious Diseases: Pathogen diversity and the basis of host-adaption and virulence, Virus Life Cycles at Multiple Scales: Virus-host interactions controlling species-specific outcomes, G6814561078, G7723242610, G8626121027, G8674210727, Identification of factors driving the emergence and spread of avian influenza viruses with zoonotic potential (FluSWITCH), Virus Life Cycles at Multiple Scales: Biology of virus-infected cells
OpenAlex ID: W7124428125