An interdisciplinary team of researchers at the Institut Pasteur and the Georgia Institute of Technology has received a $2.5 million National Institutes of Health (NIH) grant to study phage therapy. This project aims to deepen the fundamental knowledge and the clinical potential of bacteria-killing viruses – also called bacteriophage, or phage –, to treat antibiotic-resistant infection.
Over the five years of the award, Laurent Debarbieux of the Institut Pasteur, in Paris, and Joshua Weitz of the School of Biological Sciences at Georgia Tech will jointly lead teams in the U.S. and France to research interactions between bacteriophage and the host’s immune response in treating acute respiratory infections caused by multi-drug-resistant bacteria.
Phagotherapy, a potential solution against antibiotic resistance
The spread of antibiotic-resistant pathogens represents a significant public health challenge. This is why the Institut Pasteur is devoting one of its research priorities to antimicrobial resistance in its strategic plan for 2019-2023. In response to this challenge, scientists and clinicians are exploring alternative ways to cure bacterial infections caused by antibiotic-resistant germs that cannot be treated with antibiotics. One approach is to use bacteriophage, viruses which exclusively infect and eliminate bacteria. In a 2017 study published in Cell Host and Microbe, the teams of Joshua Weitz and Laurent Debarbieux showed that a synergy between an infected animal’s immune system and phage is essential to curing an infection.
Phagotherapy, therapeutic mechanisms to deepen
Advancing the fundamental understanding of phage therapy will help advance its robust and reliable use in the clinic. The five-year NIH grant (1R01AI46592-01; Synergistic Control of Acute Respiratory Pathogens by Bacteriophage and the Innate Immune Response) will enable the U.S. and French teams to examine the dynamics of the synergy between phage and the immune response in treating acute respiratory infections.
“This project represents an important opportunity to integrate mathematical modeling into the foundations of phage therapy research,” Joshua Weitz says. “We look forward to extending our ongoing collaboration with the experimental phage therapy team led by Laurent Debarbieux to iteratively refine a mechanistic understanding of how phage therapy works in vivo and to develop candidate approaches to deploy phage therapy in translational settings.”
"Better understanding and therefore better control of phagotherapy is an essential step to use it better in clinical practices," says Laurent Debarbieux. "Our collaboration with the Theoretical Ecology and Quantitative Biology team, led by Joshua Weitz, will allow us to understand all the parameters involved in the effectiveness of phagotherapy".
To achieve their goals, the principal investigators will combine mathematical modeling (at Georgia Tech) and animal experiments (at the Institut Pasteur). Building on their 2017 findings, they will examine the tripartite interactions between therapeutic phage; innate immune cells (neutrophils); and multi-drug-resistant Pseudomonas aeruginosa bacteria in an in vitro system and an acute respiratory pneumonia mouse model system. The project will focus on understanding and optimizing synergistic interactions between phage and neutrophils in eliminating bacteria, even when the animal host’s immune response is impaired.
Overall, this project aims to provide a framework for advancing principles of phage ecology and innate immunology in the rational design of phage therapy for therapeutic use.