Unraveling the interactions of phage therapy, microbiota, and immunity against multi-drug resistant bacteria

Antibiotic resistant bacteria are bugs that developed ways to inactivate antibiotics created to kill them. The overuse of antibiotics in hospitals and agriculture has led to the 'post-antibiotic era', where bacteria have overcome all the antibiotics available to us. Generating new antibiotics is slow and expensive, yet alternatives must be rapidly found, as bacterial infections, if left untreated, can result in fatal outcomes. Bacteriophages, viruses that specifically target bacteria without affecting eukaryotic cells, have been proposed as antimicrobial treatment1. They replicate rapidly within bacterial cells, leading to bacterial lysis and death. In recent years, phage therapy has regained attention due to advancements in genetic engineering that enables manipulation of bacteriophages. Indeed recently, an oral phage cocktail was used to suppress multi-drug resistant Klebsiella pneumoniae, a bacterium shown to contribute to the onset of inflammatory bowel disease. This phage cocktail is now undergoing a phase II clinical trial in hundreds of patients. But, despite being phages already sporadically used in clinic, we still have to improve their therapeutic application. In fact, bacteria become resistant to phages, as they do for antibiotics; also, phages can be attacked by the patient's immune system despite being safe, with a decrease in their therapeutic effect. This project has the goal to study, for the first time, interactions between phages, bacteria, and the mammalian immune system in in vivo models. We will create engineered bacteria and employ murine models and 'omics' technologies to shed light on the phage-microbiome- host immune system interactions, to improve the use of phage therapy in vivo.