Viral tropism is a cornerstone in the spread and spillover of avian influenza viruses.

In recent years, high pathogenicity avian influenza viruses (HPAIVs) have spread among wild, captive, and domestic birds, as well as mammals. Beyond the resulting economic and ecological losses, spillover into mammals has raised concerns about a potential pandemic. Viral tropism refers to the spectrum of host species, organs, and cells susceptible and permissive to viral infection. It is a potent driver of infection dynamics and shedding patterns, which presents important variations both between and within hosts: in poultry, HPAIV leads to systemic endothelial infection in domestic chickens, whereas neurological and selective epithelial infections are observed in domestic ducks. In mammals, infection can result in respiratory and neurological disease, but the recent outbreaks in domestic dairy cows highlighted a unique and remarkable adaptation to the mammary gland prone to viral shedding in milk. The present review explores viral tropism of HPAIV across recent spillover from birds to mammals and discusses its critical involvement in viral ecology, requiring the constant surveillance and adaptation of control measures.