Gotowa bibliografia na temat „Mycobacterium leprae – Vietnam”

ABSTRACT A serological diagnostic test using phenolic glycolipid-I (PGL-I) developed in the 1980s is commercially available, but the method is still inefficient in detecting all forms of leprosy. Therefore, more-specific and -reliable serological methods have been sought. We have characterized major membrane protein II (MMP-II) as a candidate protein for a new serological antigen. In this study, we evaluated the effectiveness of the enzyme-linked immunosorbent assay (ELISA) using the MMP-II antigen (MMP-II ELISA) for detecting antibodies in leprosy patients and patients' contacts in the mid-region of Vietnam and compared to the results to those for the PGL-I method (PGL-I ELISA). The results showed that 85% of multibacillary patients and 48% of paucibacillary patients were positive by MMP-II ELISA. Comparison between the serological tests showed that positivity rates for leprosy patients were higher with MMP-II ELISA than with PGL-I ELISA. Household contacts (HHCs) showed low positivity rates, but medical staff members showed comparatively high positivity rates, with MMP-II ELISA. Furthermore, monitoring of results for leprosy patients and HHCs showed that MMP-II is a better index marker than PGL-I. Overall, the epidemiological study conducted in Vietnam suggests that serological testing with MMP-II would be beneficial in detecting leprosy.

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10−9; OR = 0.51 [95% CI 0.40 − 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

Background and Objectives: Leprosy remains an important health problem worldwide. It is one of the oldest recorded diseases of humankind. In this study, we expanded the analysis of the geographic distribution of Mycobacterium leprae by investigating SNPs and rpoT genotypes in South Central Coast and Central Highlands clinical isolates, providing insights into the distribution and transmission of leprosy in Vietnam and in this geographic region. Materials and Methods: 27 clinical isolates from the patients, determined the genotypes of M. leprae by SNP and rpoT polymorphism. SNP genotyping was performed by PCR amplification and sequencing, rpoT genotyping by PCR amplifica- tion and electrophoresis. Results: All of 27 DNA samples (100%) were positive with RLEP TaqMan PCR (Ct value range is 18-32 on 3 replicates). SNP type 1 was identified in 15 isolates (56%), while SNP type 3 was detected in 12 samples (44%). SNP type 2 and type 4, were not detected. The 6-base repeat region of the rpoT gene was amplified by PCR and analyzed by 4% MetaPhor™ agarose gel electrophoresis. All isolates yielded amplification products of 91-bp, but not 97-bp. Conclusion: This study showed that 56% of isolates belonged to type 1, 44% to type 3. In addition, all samples have the 3-copy hexamer genotype in the rpoT gene.

La lèpre, maladie infectieuse chronique causée par Mycobacterium leprae, affecte principalement la peau, les nerfs et les yeux avec des séquelles majeures en l’absence de traitement. Avec 200 000 nouveaux cas diagnostiqués chaque année (1 toutes les 2 minutes), il s’agit de la mycobactériose la plus commune après la tuberculose et requalifiée « maladie tropicale négligée » en 2017 par l’Organisation Mondiale de la Santé (OMS). Si la contribution génétique de l’hôte dans l’histoire naturelle de la maladie est maintenant bien établie, son architecture reste lacunaire. Dans cette continuité et afin de la préciser, nous avons, pour la première fois, utilisé une approche de génétique épidémiologique familiale. Plus précisément, nous avons réalisé la première étude d’association pangénomique (Genome-Wide Association Study, GWAS) familiale sur la lèpre. Ainsi, au cours des 20 dernières années, un échantillon de 481 familles nucléaires, parents et enfants, sélectionnées à partir d’un enfant atteint, a été constitué au Vietnam. Sur cet échantillon primaire de 1749 individus incluant 622 enfants atteints, nous avons testé l’association de près de 6 millions de variants bi-alléliques (Single Nucleotide Polymorphism, SNP), génotypés ou imputés, avec la lèpre. Dans un second temps, nous avons testé les signaux les plus prometteurs dans un échantillon de réplication, c’est-à-dire, indépendant et issu de la même population, constitué de 1 181 cas et 668 contrôles. Les résultats les plus significatifs ont été observés au sein de la région HLA et l’analyse multivariée a permis d’identifier trois signaux indépendants. Deux dans la région HLA classe I : rs1265048 [Odds-ratio (OR) = 0,69 ; p-val = 5,5.10⁻¹¹] et rs114598080 [OR = 1,47 ; p-val = 8,8.10⁻¹³] ; Et un dans la région HLA classe II : rs3187964 [OR = 1,67 ; p-val = 8,4.10⁻¹⁶]. Nous avons également identifié deux signaux hors HLA : un variant faux-sens dans le gène LACC1 (rs3764147 : OR = 1,52 ; p-val = 5,1.10⁻¹⁴), et un variant à proximité du gène IL12B (rs6871626 : OR = 0,73 ; p-val = 6.4.10⁻⁸). Les contraintes de coûts des études pangénomiques imposent une réduction majeure du nombre de SNPs à tester dans d’autres échantillons. Dans les études familiales, les parents sont de fait génotypés et pourraient permettre une réplication immédiate sans coûts ajoutés. Au moyen d’une large étude de simulation, nous avons montré que cette approche était pertinente. Une étude cas-contrôle chez les parents de l’échantillon primaire est une réplication valide, statistiquement indépendante de l’étude d’association familiale. C’est un argument fort en faveur des approches familiales pour l’exploration pangénomique de la contribution génétique de l’hôte dans les phénotypes complexes. La compréhension de la physiopathologie de l'infection à M. leprae est cruciale pour optimiser les approches préventives selon les profils génétiques à plus haut risque, et ouvrir de nouvelles pistes thérapeutiques en précisant les cascades fonctionnelles pertinentes. En ce sens, la dissection du contrôle génétique de l'infection par l'hôte est indispensable. Enfin, remettre la famille au cœur de la quête génétique, c’est remettre la génétique dans son milieu naturel
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It primarily affects the skin and peripheral nerves, and can cause an irreversible impairment of nerve function, often leading to severe disabilities and social stigma if left untreated. The disease, re-qualified by WHO (World Health Organization) as a “Neglected Tropical Disease” in 2017, remains a major public health problem in regions of endemic countries, with over 200,000 new cases per year (one every two minutes). It is ranked second as the most common mycobacterial infectious disease, right after tuberculosis. While it has been well established that there is a genetic contribution to this disease, the underlying genetic causes remains unknown. In our study, we sought to reveal the host´s genetic architecture of leprosy by taking of a familial epidemiological approach. We conducted the first Family-Based Genome-Wide Association Study (GWAS) of leprosy in 481 Vietnamese nuclear families (parents and children) selected based on one affected child and collected over the past 20 years. Using this sample of 1,749 individuals, including 622 affected offspring, we performed association tests between six million biallelic genetic variants (Single-Nucleotide Polymorphism, genotyped or imputed) and the binary phenotype of disease status. Following this first analysis, we conducted a replication analysis of the most promising results in an independent sample of the same ethnic origin, accounting for 1,181 cases and 668 controls. The most significant results were observed within the HLA (Human Leukocyte Antigen) region, in which 3 independent SNPs displayed genome-wide significant associations. Among these, two were for the HLA class I region and one for the HLA class II (rs1265048 [OR = 0.69; p-value = 5.5x10⁻¹¹], rs114598080 [OR = 1.47; p-value = 8.8x10⁻¹³] and rs3187964 [OR = 1.67; p-value = 8.4x10⁻¹⁶] respectively). We also identified a missense variant in the LACC1 gene (rs3764147: OR = 1.52; p-value = 5.1x10⁻¹⁴) and an intergenic variant located close to the IL12B gene (rs6871626: OR = 0.73; p-value = 6.4x10⁻⁸). LACC1 encodes a central regulator of the metabolic function and bioenergetic state of macrophages and IL12B encodes IL-12p40, which is common to two interleukins, IL-12 and IL-23. Large GWAS are expensive, strongly limiting the number of variants to test in a replication set. Here, we took advantage of the available parental phenotypic and genotypic information to perform a classical case-control study among the parents of the family-based sample. Indeed, using of extensive computer simulations, we demonstrated that this population-based parental study is a valid, powerful and costless replication strategy to confirm family-based associations. Overall, our observations add to the attractiveness of family-based designs and should provide valuable help for investigators planning to perform GWA studies. Understanding leprosy pathophysiology infection is crucial to optimize preventive approaches based on genetic profiles. Dissection of the genetic control of the infection by M. leprae by its human host, therefore, constitutes an indispensable step. Finally, repositioning the family at the heart of the genetic quest means repositioning genetics into its natural environment