Descrizione del progetto
Scoprire i meccanismi dell’immunità dei batteriofagi
I batteriofagi sono virus che infettano i batteri. Poiché i batteri sono in grado di sviluppare meccanismi di immunità per resistere all’infezione dei batteriofagi, anche i batteriofagi possono sviluppare meccanismi di controresistenza. Si tratta di una sorta di corsa evolutiva agli armamenti. Il progetto DEFEND, finanziato dal CER, si propone di sviluppare strategie terapeutiche efficaci per trattare i patogeni resistenti agli antibiotici sulla base di batteriofagi. Indagherà in che modo il sistema immunitario adattativo (CRISPR) e quello innato proteggono i batteri dai virus batterici (fagi) a livello molecolare, cellulare e di popolazione.
Obiettivo
Microbes are engaged in an evolutionary arms-race with their viruses and have evolved a spectrum of adaptive and innate defense systems to limit viral predation. Mechanistic insights into defense systems have yielded truly revolutionary genetic tools ranging from CRISPR-based genome editing nucleases to restriction enzymes used for molecular cloning. Despite the ongoing effort to understand defense systems, many antiviral defense systems remain virtually unstudied in and outside their native microbial context, creating huge potential for scientific breakthroughs and development of further game changing applications.
In the timely research proposed here I aim to uncover how adaptive (CRISPR) and innate immune systems protect bacteria from bacterial viruses (phages) at the molecular, cellular and population level. Based on our exiting unpublished observation that extremely phage resistant pathogens in our bacterial strain collection are true collectors of defense systems, I propose to investigate the contribution of each defense system and cooperativity between defense systems for broad and specific bacteriophage resistance. I furthermore aim to determine the molecular mechanism of a dominant set of related innate immune systems found in clinical pathogens, and to reveal how individual phages achieve immune evasion.
To accomplish my goals, I plan to use an interdisciplinary approach combining state-of-the-art molecular microbiology and biophysics at the single molecule and single cell level, with bioinformatics and high-throughput synthetic genomics screens. The project may lead to fundamentally new insights into the mechanism and evolution of virus immunity and will further explore the genetic treasure trove at the interface of virus and host interactions. Our findings will have implications for controlling virus resistance, and will be vital to develop effective therapeutic strategies to treat antibiotic resistant pathogens based on bacteriophages.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
2628 CN Delft
Paesi Bassi