Clinical human metapneumovirus isolates show distinct pathogenesis and inflammatory profiles but similar CD8 + T cell impairment.

replication. Clinical isolates are collected directly from human patients and have undergone <10 passages, serving as more physiologically relevant models of HMPV infection. Additionally, existing animal studies of HMPV disease mainly focus on lung pathogenesis, while HMPV infects both upper and lower airways of humans. This work highlights distinct differences in HMPV burden in upper and lower tracts between clinical isolates. Lastly, this study uniquely explores differences in host immunity between all four HMPV genetic lineages. The predominant HMPV subtype in circulation varies seasonally; thus, understanding host responses to all subgroups is critical for developing effective HMPV vaccines.