Descrizione del progetto
Proteine di membrana utilizzate per combattere i batteri che causano la tubercolosi
Molte proteine di membrana svolgono un ruolo nella segnalazione e nel riconoscimento cellulare. Il progetto PANDORA, finanziato dall’UE, prevede di sfruttare le proteine di membrana in tre diversi modi per uccidere i batteri che causano la tubercolosi (Mycobacterium tuberculosis) e stimolare una risposta immunitaria duratura. Il micobatterio induce cambiamenti nell’espressione delle proteine di membrana sulle cellule infette. Esso esprime anche proteine di membrana che sono riconosciute da proteine di membrana, denominate autolisine, espresse su micobatteriofagi (virus che infettano i micobatteri). Nella cura di PANDORA, vescicole di nanoparticelle altamente selettive, i polimersomi, identificheranno le cellule infette in base ai loro biomarcatori di membrana. Essi forniranno quindi anticorpi di fusione contenenti la sequenza di legame delle autolisine «fuse» a una molecola terapeutica per identificare ed eliminare i batteri. Infine, cellule T ingegnerizzate che riconoscono gli antigeni sulle cellule infette aumenteranno l’immunità a lungo termine.
Obiettivo
I propose here a research vision that aims to revolutionise the way we cure infections caused by intracellular pathogens, with the aim to find a universal therapy to infectious diseases that will also counteract the development of drug resistance. In PANDORA, I will specifically focus on eradicating human tuberculosis, one of the worst pandemics so far. To do this, I will first probe what are the molecular ‘bar-codes’ of infected cells, namely those specific membrane proteins that cells express upon infection. I will use this to reversely engineer a repertoire of super-selective polymeric nanoparticles - known as Polymersomes - that will carry ligands to recognise, bind, and selectively attack infected cells only, while leaving non-infected cells completely untouched. Such nanocarriers will access the infected cells and locally deliver their payload, which is the core technology of the therapy. Such technology will be inspired by what nature invented: I will reproduce the binding sequence of autolisins, proteins expressed by bacteriophages that specifically bind the wall of Mycobacteria species (the agent causing tuberculosis). I will thus create fusion antibodies (Ab) characterized by (i) the binding sequence of mycobacteriophages autolisins (for selective recognising intracellular Mycobacterial wall) and (ii) an effector region promoting bacterial clearance through either the macrophage-triggered phagocytosis or an ubiquitin-proteasome system. This therapy will represent a complete revolution in the field of new antimicrobial development, as it will combine complete bacterial eradication, development of memory immunity and fight against drug resistance, the three core pillars of this project.
The super-selective polymersomes carrying the Abs-based universal therapy will be combined with the development of chimeric antigen receptor T-cells (CAR-T) against infection. These T-cells will be designed to chase and eradicate circulating infected cells in model organism.
Campo scientifico
- medical and health scienceshealth sciencesinfectious diseases
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicinepneumologytuberculosis
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
20122 Milano
Italia