Descrizione del progetto
Micobatteri a crescita lenta responsabili della persistenza della tubercolosi
La tubercolosi rimane un’importante malattia infettiva in tutto il mondo, con oltre un milione di decessi ogni anno. Nel corso della sua evoluzione, l’agente da cui è provocata, il Mycobacterium tuberculosis, sembra aver acquisito un fenotipo a crescita lenta, che ha probabilmente contribuito all’estremo successo del batterio come patogeno umano. Il progetto Slow growth, finanziato dall’UE, decifrerà i meccanismi molecolari responsabili di questo cambiamento nel tasso di crescita rispetto ai micobatteri ancestrali. Attraverso la manipolazione genetica delle varianti Mycobacterium canettii, strettamente correlate ma a crescita veloce, e per mezzo di test fenotipici, i ricercatori analizzeranno gli eventi evolutivi che hanno prodotto un tale cambiamento. I risultati forniranno informazioni sulla virulenza e sulla persistenza dei micobatteri e apriranno la strada a strategie più efficaci per il trattamento della tubercolosi.
Obiettivo
Tuberculosis (TB) is an infectious disease caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), responsible for 1.5 million deaths per annum. Moreover, due to the ability of Mtb to persist in the host, a further one third of the world population is latently infected and at risk for disease later in life. So far, the major vaccine against TB (Bacille Calmette-Guérin vaccine) has a limited impact on the global TB epidemic, as it does not always prevent pulmonary infections in adults. Furthermore, drug resistant strains have emerged and spread worldwide, threatening to render the actual 6-month treatment ineffective. In this context, studying the molecular mechanisms underlying mycobacterial virulence and persistence are crucial to develop new strategies to treat TB.
A hallmark of Mtb is its slow growth rate. Recent phylogenetic studies have demonstrated that ancestral mycobacteria were first fast-growing bacteria, before an evolutionary separation into fast- and slow-growing mycobacteria. Intriguingly, all the main human mycobacterial pathogens, including Mtb, are slow-growers, suggesting the importance of slow-growth as a successful evolutionary step to become professional human pathogens. Using cutting-edge multidisciplinary approach, combining real-time single cell techniques and genetic approaches, I will, in collaboration with the Brosch lab, decipher the molecular mechanism(s) which led to the evolution of Mtb towards a slower growth, by taking advantage of the fast-growing M. canettii, closely related to the ancestor of Mtb and genetically tractable. I will also directly investigate the biological importance of slow growth on the virulence and persistence of Mtb by genetically engineering Mtb strains with different growth rates. Altogether, this work will lead to new perspectives and insights into host-Mtb interaction, important for the development of innovative therapeutic approaches.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
75724 Paris
Francia