Description du projet
Des mycobactéries à croissance lente responsables de la persistance de la tuberculose
La tuberculose reste une maladie infectieuse importante dans le monde, avec plus d’un million de décès chaque année. Au cours de son évolution, l’agent infectieux Mycobacterium tuberculosis semble avoir acquis un phénotype de croissance lente, ce qui a probablement contribué à faire de cette bactérie un pathogène humain très performant. Le projet Slow growth, financé par l’UE, permettra de déchiffrer les mécanismes moléculaires responsables de cette modification du taux de croissance par rapport aux mycobactéries ancestrales. À l’aide de manipulations génétiques de variantes de Mycobacterium canettii étroitement apparentées, mais à croissance plus rapide, et d’essais phénotypiques, les chercheurs dissèqueront les événements évolutifs qui ont conduit à un tel changement. Les résultats permettront de mieux comprendre la virulence et la persistance des mycobactéries et ouvriront la voie à des stratégies plus efficaces pour le traitement de la tuberculose.
Objectif
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
75724 Paris
France