Deciphering host-pathogen interactions to eradicate intracellular mycobacteria pathogens: key drivers to design new precision nanomedicine tools

This project intends to establish a new paradigm in the way we approach infectious diseases due to intracellular pathogens. It will provide a new approach to study host-pathogens interactions with the aim of designing target to definitely eradicate parasites, and to eliminate drug resistance. The project will be specifically focused on two of the most representative intracellular pathogens. One is the - the etiologicalM. tuberculosis (Mtb) agent of human tuberculosis (TB). Furthermore, our approach will be also validated using – an opportunistic pathogen taking its tolls among cystic fibrosis (CF) patients. The reason behindMycobacterium abscessus (Mab) the focus on TB relies on the fact that there are ca.10.4 millions new TB cases per year, with an average killing rate of 1.3 million people annually (TB kills 3 people/minute). In addition to TB, the recent incidence of non-tuberculous Mycobacteria (NTM) infections in CF patients has indeed raised from 3.3% to 22.6%, increasing morbidity and mortality associated with these pathogens [Martiniano, 2019]. Among NTM subspecies, Mab is becoming the most prominent pathogen in CF centers worldwide [Johansen, 2020]. drug therapy takes up to 2 years, with only about 30% of success rate [Van Dorn, 2017]. Its failed eradication leads to anMab accelerated lung function decline. For this reason, -infected CF patients are even excluded from lung transplant lists [Degiacomi, 2019]. ’s success in becoming an emerging CF pathogen is due to the followingMab Mab reasons: (i) possible direct person-to-person transmission [Bryant, 2016], (ii) biofilm and drug resistance [Wu, 2018], (iii) Association between CFTR (cystic fibrosis transmembrane conductance regulator) mutations and formation of granuloma in the presence of infection [Bernut, 2019], (iv) lack of active drugs (in particular with bactericidal activity) [Degiacomi, 2019], (v) new definitive strategies against both pathogens are thusMab extremely needed. It is evident that these challenges cannot be effectively addressed by applying efforts coming from a single research subject. We believe that a multidisciplinary-inspired cooperative effort is absolutely needed to face these problems. We thus propose here to combine complex biological functions, namely molecular microbiology together with phage display, secretome analyses and super-selectivity to create a pioneering precision nanomedicine tool that possess the necessary requirements for clinical translation. We are confident that by the end of the 3 years we will have produced a completely new paradigm in drug delivery, by bridging cutting-edge soft matter physics, molecular biology and biophysics into preclinical science. This project has one very much focused aim: to seek solutions TO END intracellular mycobacteria related infections.