Bacteriophages modulate macrophage functions and immune responses in therapeutic applications

The increasing problem of antibiotic resistance is one of the most significant threats to global public health, contributing to higher mortality rates, prolonged hospitalizations, and rising healthcare costs. As a response to this challenge, phage therapy – based on the use of bacteriophages (phages), viruses that selectively infect and lyse bacteria – has emerged as a promising alternative. In recent years, increasing interest in phage therapy has been observed in both preclinical and clinical research. Accordingly, increasing attention is being directed toward investigating potential interactions between phages and mammalian cells. Bacteriophages, like other exogenous particles introduced into the human body, are subject to innate and adaptive immune mechanisms. This review places particular emphasis on interactions between phages and macrophages. On the one hand, their significant participation in the clearance of therapeutic phages is described, which may reduce the effectiveness of antibacterial treatment; nevertheless, this mechanism is considered to be an indirect way of autotolerance of intestinal phages. From another perspective, bacteriophages, as nucleoprotein molecules, can induce various immunomodulation mechanisms, which may find clinical applications in the future. Their involvement in macrophage polarization, induction of the secretion of pro- and anti-inflammatory cytokines, and modulation of phagocytic functions are briefly discussed. Apart from their therapeutic importance, studying the interactions of phages with eukaryotic cells, such as immunocompetent cells including macrophages, may also help explain their indisputable role in maintaining homeostasis as integral components of the human microbiota.