Efficient airborne transmission of influenza D virus in ferret models and serological evidence of human exposure in Northeast China

Newly emerging influenza D virus (IDV), first identified in swine in 2011, has demonstrated broad mammalian tropism with notable prevalence in bovine populations and occupational exposure-associated seroprevalence among cattle workers. This zoonotic expansion raises concerns that IDV could acquire capability for human-to-human transmission via sustained evolving in mammal hosts. Here, we evaluated the infectivity and transmissibility of a currently circulating IDV strain, D/bovine/Jilin/HY11/2023 (abbreviated as D/HY11), isolated from cattle in Northeast China in 2023. D/HY11 was able to replicate efficiently in human primary respiratory epithelial cells and exhibits respiratory tract tropism in mammals. More importantly, we found that D/HY11 could efficiently transmit through the air between ferret models (5/6). Serological surveillance (2020-2024) revealed alarming exposure rates, with no significant difference in positivity between rural and urban populations: 73.37% (449/612) in the general population and an even higher rate of 96.67% (58/60) among individuals with respiratory symptoms. The extraordinary high IDV seropositivity among people in Northeast China highlights the possibility of silent spread in mammals with mild symptoms. Among generic anti-influenza drugs tested in vitro, only polymerase inhibitors demonstrated effective suppression of IDV replication. And the D/HY11 strain exhibited enhanced polymerase activity compared to the classical IDV strain, with preliminary evidence implicating the P3 gene as a potential contributing factor to this functional enhancement. Our pathogenetic and serological findings indicate that IDV may have acquired the capacity for human-to-human transmission during its ongoing evolution, and currently circulating IDV strains already pose a potential panzootic threat.