The lung environment of people with cystic fibrosis (pwCF) is characterized by excessive inflammation and the inability to resolve bacterial infections, which can lead to increased complications and eventually mortality. Alveolar macrophages (AMs) are immune cells resident in the lungs, whose job is to sense external threats like bacterial pathogens and coordinate a response that leads to disinfection. Sometimes, AMs are unable to eliminate bacteria and this leads not only to a persistent infection, but also to an overreaction that further damages the lung tissue. Among all the pathogenic microorganisms, Mycobacterium abscessus (Mab) often thrives in the lungs of patients affected by CF. Importantly, this deadly pathogen also has the natural ability to counteract the activity of many drugs.
This project will focus on “re-educating” AMs to respond more efficiently to Mab infection by using drugs that modify how the genetic information, contained in the DNA, is read and interpreted by the cells. The effect of these drugs, called epidrugs, will be determined by biomolecular, microbiological and biochemical analyses on either just the cells or the whole mouse infected by Mab. Importantly, we will be using molecules that have already been declared as “safe for Humans” and are already administered to patients with other diseases like cancer, diabetes and HIV. In this way, we hope to increase the safety of the treatment while reducing the possible time needed before clinical application. Using this approach, we will promote the natural ability of the infected cells to deal and eliminate the bacteria achieving a new type of therapy. Such a strategy, called “host-directed therapy”, is also very innovative as it acts on the cells hosting the bacteria, so the bacteria itself is stopped from adjusting and fighting back the therapy.