Description du projet
La génétique des pathogènes à l’origine des formes cliniques de la lèpre
La lèpre est causée par Mycobacterium leprae et Mycobacterium lepromatosis, qui sont difficiles à étudier, car elles ne peuvent pas être cultivées en laboratoire. Le séquençage récent de différents isolats bactériens a identifié des gènes hypermutés avec des rôles potentiels dans la résistance aux médicaments et l’adaptation des espèces. Le projet LEPVORS, financé par l’UE, vise à associer ces changements génétiques au phénotype clinique et à la résistance aux médicaments. De plus, en utilisant les progrès moléculaires récents comme le séquençage de nouvelle génération, les chercheurs étudieront des souches supplémentaires isolées de formes cliniques plus rares de la lèpre. Les résultats fourniront un aperçu sans précédent de la biologie et de l’adaptation à l’hôte de l’agent pathogène de la lèpre.
Objectif
Leprosy is a multiform infection caused by Mycobacterium leprae, an uncultivable bacLeprosy is a slow and chronic infection caused by Mycobacterium leprae. Recent advances in the next generation sequencing offer a new possibility to study the physiopathology of M. leprae, an uncultivable bacteria on anexic media. In 2018, the comparative analysis of 154 M. leprae genomes from 25 countries identified three hypermutated genes including two (ribD and fadD9) probably associated with drug-resistant and the most mutated one being ml0411 with a potential role in host adaptation. In a mycobacterial species, like M. leprae, with such a reduced number of coding genes, it is reasonable to assume that this high rate of mutations probably led to the modification of essential biological functions. In addition, the recent development of more efficient molecular tools can now help to obtain the whole genome sequencing of the strain from the low representative forms of the disease. This could help to identify more of these highly mutated genes and establish a link between the pathogen genetic and the clinical disease outcome. This project proposes to functionally characterize some of the mutations identified but also to identify new candidates which could be linked with differences in host phenotype. The study has three specific aims: Specific aim 1 will focus on potential new genes involved in M. leprae drug resistance. Using surrogate mycobacteria such as M. tuberculosis and M. haemophilum, we will test the drug susceptibility of mutated strains in fadD9 and ribD compared to wild-type strains. In specific aim 2, we will investigate the role of ml0411 and mutated version on the host innate immune response modulation In specific aim 3, we will focus on the whole genome sequencing of M. leprae strain from the less represented clinical form of leprosy, the tuberculoid pole to identify new genetic differences in the bacteria which could be associated with different host phenotypes.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-GF - Global FellowshipsCoordinateur
4123 Allschwil
Suisse