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<p>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 &gt;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.</p>

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The potential of H5N1 viruses to adapt to bovine cells varies throughout evolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Matthew L. Turnbull,
  • Mohammad Khalid Zakaria,
  • Nicole S. Upfold,
  • Siddharth Bakshi,
  • Callum Magill,
  • Udeet Ranjan Das,
  • Andrew T. Clarke,
  • Laura Mojsiejczuk,
  • Vanessa Herder,
  • Kieran Dee,
  • Nancy Liu,
  • Monika Folwarczna,
  • Georgios Ilia,
  • Wilhelm Furnon,
  • Verena Schultz,
  • Hanting Chen,
  • Ryan Devlin,
  • Jack McCowan,
  • Alex L. Young,
  • Wai-Wai Po,
  • Katherine Smollett,
  • Muhammad Ahsan Yaseen,
  • Rebecca Ross,
  • Avanti Bhide,
  • Bianca van Kekem,
  • Ron A. M. Fouchier,
  • Ana da Silva Filipe,
  • Munir Iqbal,
  • Ed Roberts,
  • Joseph Hughes,
  • Dirk Werling,
  • Pablo R. Murcia,
  • Massimo Palmarini

摘要

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.