Projektbeschreibung
Die Genetik der Krankheitserreger hinter klinischen Lepraformen
Lepra wird durch das Mycobacterium leprae und das Mycobacterium lepromatosis verursacht, die nur schwer zu untersuchen sind, da sie im Labor nicht gezüchtet werden können. Die jüngste Sequenzierung verschiedener bakterieller Isolate hat hypermutierte Gene identifiziert, die möglicherweise eine Rolle bei der Medikamentenresistenz und der Anpassung der Spezies spielen. Das Ziel des EU-finanzierten Projekts LEPVORS ist es, diese genetischen Veränderungen mit dem klinischen Phänotyp und der Medikamentenresistenz in Zusammenhang zu bringen. Des Weiteren werden die Forschenden unter Verwendung neuester molekularer Erkenntnisse wie der Sequenzierung der nächsten Generation weitere Stämme untersuchen, die aus selteneren klinischen Formen der Lepra isoliert wurden. Die Ergebnisse werden einen bislang unerreichten Einblick in die Biologie und Wirtsanpassung des Erregers der Lepra geben.
Ziel
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.
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MSCA-IF-GF - Global FellowshipsKoordinator
4123 Allschwil
Schweiz