Macrophage-induced reduction of bacteriophage density limits the efficacy ofin vivopulmonary phage therapy

Abstract

AbstractThe rise of antimicrobial resistance has led to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused byPseudomonas aeruginosarelies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of mice without boosting theP. aeruginosaload in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels ofP. aeruginosawere significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we developed a mathematical model. Integration of model simulations suggest that AM reduce bacteriophage density in the lungs. We experimentally confirmed that thein vivodecay of phage is faster in immunocompetent compared to AM-depleted animals. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings.