Descripción del proyecto
Una micobacteria de crecimiento lento responsable de la tuberculosis persistente
La tuberculosis sigue siendo una enfermedad infecciosa importante en todo el mundo que provoca más de un millón de muertes al año. El agente causante, «Mycobacterium tuberculosis», parece haber adquirido durante su evolución un fenotipo de crecimiento lento, lo que probablemente ha contribuido a que esta bacteria se convierta en un patógeno humano de gran éxito. El proyecto financiado con fondos europeos Slow growth descifrará los mecanismos moleculares responsables de este cambio en la tasa de crecimiento en comparación con micobacterias ancestrales. Mediante la manipulación genética de variantes de «Mycobacterium canettii» (estrechamente relacionada con «M. tuberculosis» pero de crecimiento más rápido) y ensayos fenotípicos, los investigadores analizarán minuciosamente los procesos evolutivos que condujeron a dicho cambio. Los resultados proporcionarán información sobre la persistencia y la virulencia micobacterianas y allanarán el camino a unas estrategias más efectivas para el tratamiento de la tuberculosis.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
75724 Paris
Francia