Towards the molecular epidemiology of Mycobacterium leprae: strategies, successes, and shortcomings.

Mycobacterium leprae, the causative agent of leprosy, is an unusual organism that presents unique challenges to those studying the disease through molecular epidemiology. As a consequence, many basic aspects of disease transmission and biology remain unilluminated. In this review, we explore the general principles of molecular epidemiology, and the special difficulties surrounding the application of molecular epidemiology to M. leprae. We briefly discuss the computational tools commonly employed in molecular epidemiology studies. The past decade of developments in molecular strain typing approaches through VNTRs and SNP loci, and their merits and limitations, are discussed. We summarize what has been learned about the transmission and historical origins of leprosy through molecular epidemiology and Bacterial Population Genetics, to date. Lastly, we critically evaluate the strengths and shortcomings of leprosy research, and present recommendations for future work that will hopefully shed light on some of the disease's most fundamental mysteries.

Molecular epidemiology of Mycobacterium leprae as determined by structure-neighbor clustering.

It has proven challenging to investigate the molecular epidemiology of Mycobacterium leprae, the causative agent of leprosy, due to difficulties with culturing of the organism and a lack of genetic heterogeneity between strains. Recently, a cost-effective panel of variable-number tandem-repeat (VNTR) markers has been developed. Use of this panel allows some of those limitations to be overcome and has allowed the genotyping of 475 M. leprae strains from six different countries. In the present report, we provide a comprehensive analysis of the relationships among the strains in order to investigate the patterns of transmission and migration of M. leprae. We find phylogenetic analysis to be inadequate and have developed an alternative method, structure-neighbor clustering, which assigns isolates with the most similar genotypes to the same groups and, subsequently, subgroups, without inferring how the strains descended from a common ancestor. We validate the approach by using simulated data and detecting expected epidemiological relationships from experimental data. Our results suggest that most M. leprae strains from a given country cluster together and that the occasional isolates assigned to different clusters are a consequence of migration. We found three genetically distinguishable populations among isolates from the Philippines, as well as evidence for the significant influx of strains to that nation from India. We also report that reference strain TN originated from the Philippines and not from India, as was previously believed. Lastly, analysis of isolates from the same families and villages suggests that most community infections originate from a common source or person-to-person transmission but that infection from independent sources does occur with measurable frequency.