Seminarios IHSM La Mayora - Luis Serrano (CRG, Barcelona)

Engineering bacteria to locally deliver therapeutic agents or to present antigens for vaccination is an emerging area of research with great clinical potential. Compared to drugs, nanoparticles and phages, bacteria provide several advantages when used as a vehicle to delivery therapies: i) they contain all the necessary biological machinery to synthesise complex therapeutics; ii) complex regulatory circuits that sense and respond specifically to diseased tissue can be integrated; iii) DNA integration into the host genome is improbable; iv) proliferation can be effectively controlled using antibiotics as a contingency strategy; and v) growth can be controlled by integrating suicidal circuits or auxotrophic dependence modules. In our group, for many years we have analysed in the systems biology of the genome-reduced bacterium, MPN, a bacterium that causes mild pneumonia in humans. MPN offers an elegant approach to tackle lung diseases because it can be grown in a defined medium, it does not have a cell wall, it directly releases any secreted biomolecule into the medium, it does not recombine, and it has a unique genetic code that prevent genes from being passed onto other bacteria. We have already engineered this bacterium so that it is non-pathogenic and so that it does not cause an inflammatory response in mouse lungs. Within this bacterial chassis, we have also integrated genes encoding enzymes that are capable of dissolving bacterial biofilms caused by Gram-positive and -negative bacterial as well as and proteins that have bactericidal activity. This engineered bacterium can survive more than 4 days in the murine lung, causes no lesions, and induces a reduced inflammatory response when compared to its wildtype counterpart. We have shown that this chassis can be used to treat infectious bacterial diseases in mouse lungs, including those caused by P. aeruginosa. Here I will present how the project started, where are we know and our future plans to use it for different lung diseases.