Structural determinants of bacteriophage antigenicity

Bacteriophages – viruses that infect bacteria – were the primary method of bacterial infection control before the advent of antibiotics. Today, as the antimicrobial resistance crisis intensifies, these natural predators of bacteria are increasingly deployed as compassionate use therapeutic agents. In this so-called phage therapy, bacteriophages that specifically infect and kill a patient’s drug-resistant bacterial strain may be delivered intravenously twice per day, often for several months. One successful model of this experimental treatment involves mycobacteriophages, which specifically infect and kill Mycobacterium strains like the human pathogens M. tuberculosis and M. abscessus. Although mycobacteriophage therapy is safe and effective, its use can be limited by the strong immune response to phages administered systemically. Phage-specific antibodies not only flag the phage for rapid clearance by the immune system but can also interfere with phage therapy by sterically hindering the phage from binding to and infecting its target bacterium. Antibody responses to mycobacteriophage therapy vary widely, with factors like route of administration and the macromolecular structure of the phage playing key roles. In this presentation I will discuss the structural determinants of mycobacteriophage immunogenicity and our goal to use structure-guided engineering to design immune evasive mutant phages.