DS0408 -

Dissecting the genetic architecture of reversal/paradoxical reactions in leprosy and Buruli ulcer – MYCOPARADOX

Submission summary

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that principally infects macrophages and Schwann cells. Leprosy remains a major public health problem with more than 200,000 new cases reported in 2014. Leprosy reversal reactions (RR) correspond to acute episodes of cellular immunity in skin and/or nerves classically observed soon after the treatment was initiated and are the leading cause of permanent neurological damage. Thus, the early identification of patients at risk of RR is one of the most decisive challenges in modern leprosy care. Why only a proportion of leprosy patients undergo RR is not known. Recently, we have conducted a transcriptomic study demonstrating that RR patients have a genetically controlled disregulation of the inflammatory response against M. leprae. We hypothesized that, as observed in numerous infectious diseases, the most extreme forms of RR could result from a collection of genetically diverse single-gene inborn lesions. Our first objective is to test this hypothesis and identify the genetic variants that have a very strong effect in the development of the most severe RR by a cutting-edge strategy combining phenotypic screening for extreme forms of RR in a large sample of leprosy patients enrolled over the last 15 years and whole genome sequencing of these severe RR forms followed by ad hoc functional studies.

Buruli ulcer (BU) is another chronic mycobacterial infectious disease caused by M. ulcerans and clinically characterized by extensive destruction of the skin and soft tissues as well as bone lesions. BU incidence is increasing and is now the third most common mycobacterial disease worldwide. It is estimated that about 25% of BU patients — particularly children under the age of 15— become permanently disabled. A remarkable observation is that in ~20% of the patients who received antibiotics, antimicrobial killing is accompanied by clinical deterioration, known as paradoxical reaction (PR). Although little is known on the biological mechanisms governing this event, it is considered as an immune reconstitution inflammatory syndrome (IRIS). Our recent report of the first Mendelian cases of BU in a consanguineous Beninese family, our preliminary results of the first GWAS on BU and the observation that FVB/N mice spontaneously heal while other strains could not control the disease support the view that the considerable variability in the clinical presentation of BU – in particular the onset of PR– can be accounted for by host genetic factors. IRIS have been observed in a number of immunosuppressive conditions, however, the similarity of PR with RR is puzzling as they are both pro-inflammatory reactions following the start of antimicrobial treatment occurring in patients not known to be immuno-deficient. We hypothesize that PR observed in BU share, at least to some extent, common mechanisms with RR observed in leprosy. Our second objective is to test this hypothesis by comparing the RNAseq transcriptomic profiles observed in PR to the ones observed in RR and by assessing through association study of the largest sample of PR worldwide the role of the genes that will be identified as relevant in severe and common RR.

Our project is groundbreaking, as RR and PR are not generally thought to be genetic disorders. However, it is achievable, as it builds on strong phenotypic data, already available biological samples, powerful NGS technology, long-lasting collaboration and expertise of the two participating laboratories. This work has both immunological and clinical implications. The discovery of molecules and pathways involved in RR and PR will help us to understand the relationships between the host, antibiotics-based treatment and mycobacteria in natura. The genetic dissection of RR and PR will facilitate novel preventive and therapeutic approaches based on an understanding of the pathogenesis of these two major causes of permanent sequelae in the poorest countries of the world

Project coordination

ALEXANDRE ALCAIS (Institut National de la Santé et de la Recherche Médicale (INSERM))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM DR Paris 5 - U1163 - GHMI Institut National de la Santé et de la Recherche Médicale (INSERM)
Laboratoire de Biologie et d'Ecologie de M. Ulcerans - INSERM U892 INSERM - Laboratoire de Biologie et d'Ecologie de M. Ulcerans

Help of the ANR 418,263 euros
Beginning and duration of the scientific project: December 2016 - 36 Months

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