Identification and characterization of new drug resistance and host adaptation mechanisms in Mycobacterium leprae

Project Information

LEPVORS

Grant agreement ID: 845479

DOI

10.3030/845479

Project closed

EC signature date 24 April 2019

Start date 1 May 2019

End date 31 January 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 153 916,20

EU contribution

€ 153 916,20

Coordinated by

SCHWEIZERISCHES TROPEN UND PUBLIC HEALTH INSTITUT
Switzerland

Periodic Reporting for period 2 - LEPVORS (Identification and characterization of new drug resistance and host adaptation mechanisms in Mycobacterium leprae)

Reporting period: 2021-02-01 to 2022-01-31

Summary of the context and overall objectives of the project

Leprosy is caused by Mycobacterium leprae, which is challenging to study as it cannot be cultivated in the laboratory.
Leprosy elimination is threatened by the emergency of drug resistance and our poor knowledge of the current drug resistance mechanisms and physiopathological bacterial markers.
The recent sequencing of different bacterial isolates has identified hypermutated genes with potential drug resistance and species adaptation roles. The EU-funded LEPVORS project's scope is to characterise and associate these genetic changes with clinical phenotype, drug resistance and host response.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The LEPVOR project achieved substantial results in all work packages and three objectives.
The most important results are the linkage of mutations in two genes with dapsone resistance, including one gene involved in a compensatory mechanism and another involved directly in dapsone resistance. The results suggest a new mechanism of resistance for dapsone previously unknown. The characterization of this new mechanism is now performed, and the development of a PCR assay to efficiently detect mutations in these genes in clinical isolates.

In parallel, a total of 193 new M. leprae genomes from Brazil were sequenced, and we identified a drug resistance cluster of strains circulating in Para state, Brazil. Several SNPs are associated with this cluster and require functional characterization. The genotypes and molecular drug resistance results were communicated to the clinician, and patient treatment was adjusted accordingly. These data were also transmitted to the leprosy national program head in Brazil for further action to interrupt the transmission of drug-resistant strain in the state of Para.
The data are now used to write a publication describing the distribution of M. leprae strains in the state.

In the frame of the WP2/3, the M. leprae ML0411 and the mutated protein versions were successfully purified. The antibody response to these antigens is currently tested in Brazil.

The work performed, the knowledge acquired and methods developed during during the LEPVOR project have led to the publication of 12 peer-reviewed articles, including reviews and original research. The work performed in objective 1 led to the collection of solid preliminary data that are now used to write a grant application to characterize further the new mechanism of resistance identified in objective 1.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

LEPVORS substantially contributes to all impacts listed in the call naming 1) providing basic research data to improve our understanding of the biology and host adaptation of the causative agent of leprosy; 2) generate impact on the economic and societal levels in endemic countries by increasing new research opportunities and 3) provide a career a boost to the fellow.

Phylogenetic tree based on genomes of 263 isolates of Mycobacterium leprae