Compartmentalized cytokine networks and systemic immune remodelling in bovine mammary H5N1 infection

Highly pathogenic avian influenza A H5N1 has recently expanded its mammalian host range; in 2024, genotype B3.13 emerged in U.S. dairy cattle with pronounced mammary tropism. In the past, Influenza A virus immunology has been characterized primarily in respiratory infection models, whereas this study delineates immune responses after intramammary infection. Following intramammary H5N1 challenge of Jersey cows in the early dry-off period, an integrated characterization of dose- and compartment-specific (alveoli versus teat cistern) cytokine and chemokine profiles with peripheral leukocyte dynamics and H5- or N1-specific antibody responses was performed. The results indicate that infection-induced, quarter-restricted, monophasic inflammatory networks peak at 3–7 days post-infection, accompanied by coordinated peripheral myeloid expansion and IFN-γ–competent lymphocyte activation, and rising antibody titres across quarters.