Use of Short Tandem Repeat Sequences to Study Mycobacterium leprae in Leprosy Patients in Malawi and India

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Abstract
Inadequate understanding of the transmission of Mycobacterium leprae makes it difficult to predict the impact of leprosy control interventions. Genotypic tests that allow tracking of individual bacterial strains would strengthen epidemiological studies and contribute to our understanding of the disease. Genotyping assays based on variation in the copy number of short tandem repeat sequences were applied to biopsies collected in population-based epidemiological studies of leprosy in northern Malawi, and from members of multi-case households in Hyderabad, India. In the Malawi series, considerable genotypic variability was observed between patients, and also within patients, when isolates were collected at different times or from different tissues. Less within-patient variability was observed when isolates were collected from similar tissues at the same time. Less genotypic variability was noted amongst the closely related Indian patients than in the Malawi series. Lineages of M. leprae undergo changes in their pattern of short tandem repeat sequences over time. Genetic divergence is particularly likely between bacilli inhabiting different (e.g., skin and nerve) tissues. Such variability makes short tandem repeat sequences unsuitable as a general tool for population-based strain typing of M. leprae, or for distinguishing relapse from reinfection. Careful use of these markers may provide insights into the development of disease within individuals and for tracking of short transmission chains. Molecular typing has provided an important tool for studies of many pathogens. Such methods could be particularly useful in studies of leprosy, given the many outstanding questions about the pathogenesis and epidemiology of this disease. The approach is particularly difficult with leprosy, however, because of the genetic homogeneity of M. leprae and our inability to culture it. This paper describes molecular epidemiological studies carried out on leprosy patients in Malawi and in India, using short tandem repeat sequences (STRS) as markers of M. leprae strains. It reveals evidence for continuous changes in these markers within individual patients over time, and for selection of different STRS-defined strains between different tissues (skin and nerve) in the same patient. Comparisons between patients collected under different circumstances reveal the uses and limitations of the approach—STRS analysis may in some circumstances provide a means to trace short transmission chains, but it does not provide a robust tool for distinguishing between relapse and reinfection. This encourages further work to identify genetic markers with different stability characteristics for incorporation into epidemiological studies of leprosy.