Descripción del proyecto
La genética del patógeno detrás de las formas clínicas de la lepra.
La lepra tiene su origen en la «Mycobacterium leprae» y la «Mycobacterium lepromatosis», dos bacterias difíciles de estudiar ya que no se pueden cultivar en el laboratorio. La secuenciación reciente de diferentes cepas bacterianas permitió identificar genes hipermutados que podrían regir la farmacorresistencia y la adaptación de especies. El objetivo del proyecto LEPVORS, financiado con fondos europeos, es asociar estos cambios genéticos con el fenotipo clínico y la farmacorresistencia. Además, mediante el aprovechamiento de hitos recientes en biología molecular, como la secuenciación de nueva generación, los investigadores estudiarán cepas adicionales aisladas de formas clínicas más raras de lepra. Los resultados proporcionarán información inédita sobre la biología y la adaptación al huésped del agente causante de la lepra.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-GF - Global FellowshipsCoordinador
4123 Allschwil
Suiza