HMPV Impairs Macrophage Phagocytosis Through a Replication-Dependent Mechanism Associated with Reduced CD36 Expression and the Viral G Protein

Human metapneumovirus (HMPV) is a major cause of respiratory infections, but its impact on macrophage antibacterial functions remains poorly understood. Macrophages play a crucial role in host defense through phagocytosis, and impairment of this function may increase susceptibility to secondary infections. Here, we show that HMPV infection of THP-1-derived macrophages significantly reduces bacterial uptake in a replication-dependent manner. This effect was restricted to infected cells and was not recapitulated by cell-free supernatants, indicating a cell-intrinsic mechanism. HMPV infection was also associated with reduced expression of the scavenger receptor CD36. Viral gene knockdown studies further implicated the HMPV G protein in this phenotype, as silencing the G protein restored phagocytic function. Analysis of single-cell RNA-sequencing datasets from HMPV-infected mouse lungs revealed reduced CD36 expression and broader alterations in phagocytosis-associated gene programs across lung macrophage subsets. Supporting these observations, expression of Cd36 and Marco was reduced in lung tissue from HMPV-infected mice. Overall, these findings demonstrate that HMPV impairs macrophage-mediated bacterial uptake through a replication-dependent, cell-intrinsic mechanism and identify reduced scavenger receptor expression and the viral G protein as factors associated with this phenotype. These alterations may contribute to increase susceptibility to secondary bacterial infections during HMPV infection.