Authors: Martha Powell, Future Science Group
New research has demonstrated the host immune response is an important factor in the effectiveness of phage therapy, providing insight into the therapeutic action of bacteriophages (phages).
To date, there has been little information on how phage therapy works within hosts. Whilst in vitro studies have demonstrated the specific and effective targeting of bacteria by phages, none of these studies have investigated the mechanisms contributing to phage-mediated bacterial clearance within hosts.
The new study, published recently in Cell Host & Microbe, investigated the effects of host immunity on the efficacy of phage therapy for drug-resistant Pseudomonas aeruginosa. Two teams from the Institut Pasteur in collaboration with INSERM (both in Paris, France) and the Georgia Institute of Technology (GA, USA) used a dual approach of animal experimental and computational models to demonstrate the efficacy of phages in vivo was largely dependent on the host’s immune response, specifically neutrophils.
The teams compared the efficacies of phage application in a variety of immunocompetent and immunocompromised mouse models with P. aeruginosa respiratory tract infections. They demonstrated that phage therapy was effective in healthy mice with the immune system and phages working in synergy to fight infection. However, they observed that after 24–48 hours some bacteria developed resistance to phage killing – this was where the host innate immune system stepped in, in particular neutrophils played a dominant role, to clear acute P. aeruginosa infection.
In parallel with this, the researchers carried out in silico simulations, demonstrating that the innate immune response must destroy 20–50% of the infecting bacteria in order for phage therapy to be effective. These findings were the same for both phage-sensitive and phage-resistant bacteria, suggesting neutrophil–phage synergy is essential to resolve acute infections. First author, Dwayne Roach, a postdoc from the Institut Pasteur, commented: “Phages and the host immune system can eliminate multi-drug resistant infections, only if they work together”
This study is the first to suggest a patient’s immune status may need to be taken into account when considering phage therapy. Moving forwards, the team are planning to further examine the underlying immune mechanisms contributing to this response. Senior author, Laurent Debarbieux (Institut Pasteur) concluded: “In terms of clinical consequences, one could reconsider the selection of patients likely to benefit from phage therapy. It may not be appropriate or recommended for people with severe immunodeficiency.”
Sources: Roach DR, Leung CY, Henry M et al. Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen. Cell Host & Microb. 22(1), 38–47 e4 (2017); www.pasteur.fr/en/press-area/press-documents/phage-therapy-synergy-between-bacteriophages-and-immune-system-essential