Short-term antagonism between bacteriophages and macrophages decreases with bacteria-phage coevolution

Phage therapy, the use of viruses that infect bacteria (bacteriophages), is a promising complement to antibiotics during the antimicrobial resistance crisis, but treatment success is very variable. A key variable, which likely influences treatment outcomes, is how different immune components interact with bacteriophage, with studies finding neutrophils work synergistically while macrophages work antagonistically with bacteriophage. However, many of these studies characterize interactions and outcomes over short timescales, not considering the potential for the evolution of resistance to bacteriophages which can itself greatly affect treatment outcomes. Here, we measure how macrophages and bacteriophages affect densities and resistance evolution of the pathogen Pseudomonas aeruginosa in vitro. Consistent with previous studies, we find macrophages interact antagonistically with bacteriophages in the short term. However, this antagonism was lost following bacterial population recovery associated with rapidly evolved resistance to bacteriophages. Macrophages resulted in greater net levels of resistance and hindered increases in bacteriophage infectivity, but this did not lead to differences in bacteria-phage population dynamics. This work emphasizes the importance of characterizing the effect of the immune system on phage therapy outcomes over both shorter- and longer- timescales.