Human respiratory syncytial virus (hRSV) infection brings a wide spectrum of clinical outcomes, from a mild cold to severe bronchiolitis or even acute interstitial pneumonia. Among the known factors influencing this clinical diversity, genetic background has often been mentioned. In parallel, recent evidence has also pointed out that an early infectious experience affects heterologous infections severity. Here, we analyzed the importance of these two host-related factors in shaping the immune response in pneumoviral disease. We show that a prior gammaherpesvirus infection improves, in a genetic background-dependent manner, the immune system response against a subsequent lethal dose of pneumovirus primary infection notably by inducing a systematic expansion of the CD8⁺ bystander cell pool and by modifying the resident alveolar macrophages (AMs) phenotype to induce immediate cyto/chemokinic responses upon pneumovirus exposure, thereby drastically attenuating the host inflammatory response without affecting viral replication. Moreover, we show that these AMs present similar rapid and increased production of neutrophil chemokines both in front of pneumoviral or bacterial challenge, confirming recent studies attributing a critical antibacterial role of primed AMs. These results corroborate other recent studies suggesting that the innate immunity cells are themselves capable of memory, a capacity hitherto reserved for acquired immunity.

Pneumonia virus of mice (PVM) infection is a reference animal model for human respiratory syncytial virus (hRSV), a leading cause of lower respiratory tract disease in children under 5 years of age and in the elderly. This longitudinal study employed necropsy to examine macroscopic lesions, histological slides to assess microscopic lesions, and qRT-PCR to measure lung viral load and cytokine expression in PVM-infected mice from three different genetic backgrounds, spanning from day 1 to day 6 post-infection. Our analysis reveals a strong correlation between viral load and microscopic lesions across the 129/Sv, BALB/c, and SJL/J mouse lines, indicating that PVM pathogenicity is partially driven by the virus itself. Additionally, a significant correlation between cytokine levels and lesion severity was observed in 129/Sv and BALB/c mice, suggesting an important role of cytokines in disease progression. This study emphasizes the interplay between viral load and cytokine-driven tissue damage, with genetic background significantly influencing disease outcomes.