The rise of antibiotic-resistant superbugs poses a critical public health threat. In response, scientists and clinicians are exploring alternative approaches to cure otherwise untreatable bacterial infections.
One potential approach is to use a bacteria-killing virus, aka “bacteriophage” (phage), to treat infected patients. Phage therapy has been used for nearly a century outside the US, most prominently in Russia and Georgia (a former Soviet republic). Clinical trials to evaluate the efficacy of phage therapy are ongoing in Europe, including a wound burn treatment trial involving multiple hospitals.
In the United States, recent examples of phage-based therapeutic successes have strengthened interest in moving phage therapy from concept to clinic. A prominent example is the curative treatment of a UC San Diego professor infected by the toxin-excreting superbug Acinetobacter baumannii. Yet, many of the basic mechanisms underlying effective use of phage therapeutics remain unclear.
“The key conceptual challenge is that phage kill individual bacterial cells but not necessarily an entire population of bacteria,” says Joshua S. Weitz, professor of biological sciences and physics at Georgia Tech. “This joint project analyzed the conditions necessary for elimination of pathogen populations when host immune responses are compromised.”
In phage therapy, successful treatment has long been assumed to be due primarily to the phage’s bacteria-killing action.
Now, a joint collaborative effort between Weitz and his team at Georgia Tech, Dr. Laurent Debarbieux and Dr. James Di Santo and their teams at the Institut Pasteur, in Paris, France, find that immune cells of the animal host act synergistically with phage to cure an otherwise fatal respiratory infection in mice. The work is published in the July 2017 issue of Cell Host & Microbe.
The researchers investigated the effect of host immunity in an animal model of acute pneumonia caused by multiple-drug-resistant Pseudomonas aeruginosa – a key pathogen on the CDC serious threats list. The team, including joint first authors Dr. Dwayne Roach (Institut Pasteur) and Dr. Chung Yin (Joey) Leung (Georgia Tech), integrated pre-clinical experimental data with mathematical modeling to characterize interactions between bacteria, phage, and the immune response.
The experimental results from the pneumonia model indicate that neutrophils, an important type of white blood cell that serve as the body’s major innate defense, are essential to cure the infection during phage treatment. Leveraging results from both experiments and models, the researchers conclude that neutrophils eliminate what the phage cannot defeat: emerging, phage-resistant P. aeruginosa cells. Together, phage and neutrophils synergistically cure the acute bacterial infection.
The finding has important implications. “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”, says Dr. Debarbieux. The work will help identify phage therapeutic candidates and could also be leveraged to explore synergistic interactions between phage and immune responses in other disease contexts, like cystic fibrosis.
A second paper describing additional mathematical details of therapeutic mechanisms, jointly authored by Leung and Weitz, was published in the Journal of Theoretical Biology.