Slow growth · Deciphering the molecular mechanism(s) behind the evolution of Mycobacterium tuberculosis towards slow growth, and the impact on virulence and persistence
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-06-01 → 2023-05-31
- EU contribution
- €184,708
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Deciphering the molecular mechanism(s) behind the evolution of Mycobacterium tuberculosis towards slow growth, and the impact on virulence and persistence
Tuberculosis (TB) remains a major public health problem, with more than 1.5 million deaths per annum. An estimated further 1.7 billion people are latently infected and at risk of disease later in life. Worryingly, multidrug-resistant Mycobacterium tuberculosis strains resistant to first-line anti-TB drugs are continually emerging. The treatment of TB is very long: 6 months combining 4 antibiotics, and up to 2 years for a multidrug-resistant TB. Despite extensive drug discovery projects lead by companies and large public- private partnerships, TB remains one of the top 10 causes of human death worldwide and new strategies/treatments are needed to fight this disease. The remarkable pathogenic success of M. tuberculosis is still not fully uncovered yet but is so far mainly attributed to: (i) its immune evasion capacity, (ii) its ability to persist in the host and cause latent infection and (iii) its aerogenic transmission to other hosts from diseased individuals. Recently, it has been described that ancestral mycobacteria were first fast-growing mycobacteria, with a single major evolutionary separation into fast- and slow-growing mycobacteria. Importantly, all the major human mycobacterial pathogens belong to the slow-growing mycobacteria, compared to avirulent and environmental fast-growing mycobacteria. In this context, my project aimed to identify new mechanisms on mycobacterial virulence and persistence that are linked to the slow growth rate of M. tuberculosis, gaining fundamental insights and perspectives into host-mycobacterial interaction. This project may lead to innovative approaches to treat TB. Mycobacterium canettii appeared to be a unique resource to elucidate this question, as it presents a faster growth rate, a reduced virulence/persistence, and is known to be the closest ancestor of M. tuberculosis. To investigate how M. tuberculosis has evolved towards a slow growth lifestyle and if slow growth promotes virulence and persistence, this proposal was divided into 3 work packages: • The design of high-resolution single cell tools required to investigate growth rate, virulence and persistence of M. canettii. • A global approach to identify slow grower M. canettii mutants, before assessing their virulence and persistence. • A focused approach where mycobacterial strains are genetically modified to modulate their growth rate, before assessing their virulence and persistence.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- INSTITUT PASTEUR · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union