Influenza A viruses (IAV) have caused more documented global pandemics in human history than any other pathogen^1,2. High pathogenicity avian influenza (HPAI) viruses belonging to the H5N1 subtype are a leading pandemic risk. Two decades after H5N1 “bird flu” became established in poultry in Southeast Asia, its descendants have resurged³, setting off an H5N1 panzootic in wild birds that is fueled by (a) rapid intercontinental spread, reaching South America and Antarctica for the first time^4,5; (b) fast evolution via genomic reassortment⁶; and (c) frequent spillover into terrestrial^7,8 and marine mammals⁹. The virus has sustained mammal-to-mammal transmission in multiple settings, including European fur farms^10,11, South American marine mammals^12–15, and US dairy cattle^16–19, raising questions about whether humans are next. Historically, swine are considered optimal intermediary hosts that help avian influenza viruses (AIV) adapt to mammals before jumping to humans²⁰. However, the altered ecology of H5N1 has opened the door to new evolutionary pathways. Could dairy cattle, farmed mink, or South American sea lions serve as new mammalian gateways to humans? Here we explore the molecular and ecological factors driving H5N1’s sudden expansion in host range and assess the likelihood of different zoonotic pathways leading to an H5N1 pandemic.

在人类历史上，甲型流感病毒 (IAV) 引起的全球大流行比任何其他病原体都多^1,2 。属于 H5N1 亚型的高致病性禽流感 (HPAI) 病毒是主要的大流行风险。 H5N1“禽流感”在东南亚家禽中流行二十年后，其后代又卷土重来³ ，在野生鸟类中引发了一场 H5N1 动物疫病，并在 (a) 迅速的洲际传播的推动下，首次到达南美洲和南极洲。 ^4,5 ; (b) 通过基因组重配实现快速进化⁶ ； (c) 经常溢出到陆地^7,8和海洋哺乳动物⁹ 。该病毒在多种环境下持续在哺乳动物之间传播，包括欧洲毛皮养殖场^10,11 、南美海洋哺乳动物^12-15和美国奶牛^16-19 ，这引发了人们是否会成为下一个病毒的疑问。从历史上看，猪被认为是最佳中间宿主，可以帮助禽流感病毒（AIV）适应哺乳动物，然后再传播给人类²⁰ 。然而，H5N1 生态学的改变为新的进化途径打开了大门。奶牛、养殖水貂或南美海狮能否成为哺乳动物接触人类的新途径？在这里，我们探讨了导致 H5N1 宿主范围突然扩大的分子和生态因素，并评估了导致 H5N1 大流行的不同人畜共患途径的可能性。