Mycobacterium leprae causes leprosy. M leprae strains collected worldwide have been genetically clonal, which poorly explains the varying severity and clinical features of the disease. We discovered a new Mycobacterium species from 2 patients who died of diffuse lepromatous leprosy (DLL). The Mycobacterium was purified from heavily infected, freshly frozen autopsy liver tissue followed by DNA extraction in 1 case. Paraffin-embedded skin tissue was used for DNA extraction in another case. Six genes of the organism were amplified by polymerase chain reaction, sequenced on cloning or from amplicons, and analyzed. Significant genetic differences with M leprae were found, including a 2.1% divergence of the 16S ribosomal RNA (rRNA) gene, a highly conserved marker of bacterial evolution, and 6% to 14% mismatches among 5 less conserved genes. Phylogenetic analyses of the genes of 16S rRNA, rpoB, and hsp65 indicated that the 2 most related organisms evolved from a common ancestor that had branched from other mycobacteria. These results and the unique clinicopathologic features of DLL led us to propose Mycobacterium lepromatosis sp nov. This species may account for some of the clinical and geographic variability of leprosy. This finding may have implications for the research and diagnosis of leprosy.

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A new Mycobacterium species causing diffuse lepromatous leprosy.

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)60609-1/pdf

Free-living amoebae, a training field for macrophage resistance of mycobacteria

Leprosy, which has afflicted human populations for millenia, results from infection with Mycobacterium leprae, an unculturable pathogen with an exceptionally long generation time. Considerable insight into the biology and drug resistance of the leprosy bacillus has been obtained from genomics. M. leprae has undergone reductive evolution and pseudogenes now occupy half of its genome. Comparative genomics of four different strains revealed remarkable conservation of the genome (99.995% identity) yet uncovered 215 polymorphic sites, mainly single nucleotide polymorphisms, and a handful of new pseudogenes. Mapping these polymorphisms in a large panel of strains defined 16 single nucleotide polymorphism-subtypes that showed strong geographical associations and helped retrace the evolution of M. leprae.

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Mycobacterium leprae: genes, pseudogenes and genetic diversity

Despite the availability of effective treatment for several decades, leprosy remains an important medical problem in many regions of the world. Infection with Mycobacterium leprae can produce paucibacillary disease, characterized by well-formed granulomas and a Th1 T-cell response, or multibacillary disease, characterized by poorly organized cellular infiltrates and Th2 cytokines. These diametric immune responses confer states of relative resistance or susceptibility to leprosy, respectively, and have well-defined clinical manifestations. As a result, leprosy provides a unique opportunity to dissect the genetic basis of human in vivo immunity. A series of studies over the past 40 years suggests that host genes influence the risk of leprosy acquisition and the predilection for different clinical forms of the disease. However, a comprehensive, cellular, and molecular view of the genes and variants involved is still being assembled. In this article, we review several decades of human genetic studies of leprosy, including a number of recent investigations. We emphasize genetic analyses that are validated by the replication of the same phenotype in independent studies or supported by functional experiments demonstrating biological mechanisms of action for specific polymorphisms. Identifying and functionally exploring the genetic and immunological factors that underlie human susceptibility to leprosy have yielded important insights into M. leprae pathogenesis and are likely to advance our understanding of the immune response to other pathogenic mycobacteria. This knowledge may inform new treatment or vaccine strategies for leprosy or tuberculosis.

Leprosy and the Human Genome

Two of humankind's most socially and psychologically devastating diseases, tuberculosis and leprosy, have been the subject of intensive paleopathological research due to their antiquity, a presumed association with human settlement and subsistence patterns, and their propensity to leave characteristic lesions on skeletal and mummified remains. Despite a long history of medical research and the development of effective chemotherapy, these diseases remain global health threats even in the 21st century, and as such, their causative agents Mycobacterium tuberculosis and M. leprae, respectively, have recently been the subject of molecular genetics research. The new genome-level data for several mycobacterial species have informed extensive phylogenetic analyses that call into question previously accepted theories concerning the origins and antiquity of these diseases. Of special note is the fact that all new models are in broad agreement that human TB predated that in other animals, including cattle and other domesticates, and that this disease originated at least 35,000 years ago and probably closer to 2.6 million years ago. In this work, we review current phylogenetic and biogeographic models derived from molecular biology and explore their implications for the global development of TB and leprosy, past and present. In so doing, we also briefly review the skeletal evidence for TB and leprosy, explore the current status of these pathogens, critically consider current methods for identifying ancient mycobacterial DNA, and evaluate coevolutionary models.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajpa.21185

Tuberculosis and leprosy in perspective.

Detection of viable Mycobacterium leprae in soil samples: insights into possible sources of transmission of leprosy.

Prolonged treatment of tuberculosis (TB) often leads to poor compliance, default and relapse, converting primary TB patients into category II TB (Cat IITB) cases, many of whom may convert to multi-drug resistant TB (MDR-TB). We have evaluated the immunotherapeutic potential of Mycobacterium indicus pranii (MIP) as an adjunct to Anti-Tubercular Treatment (ATT) in Cat II pulmonary TB (PTB) patients in a prospective, randomized, double blind, placebo controlled, multicentric clinical trial. 890 sputum smear positive Cat II PTB patients were randomized to receive either six intra-dermal injections (2 + 4) of heat-killed MIP at a dose of 5 × 108 bacilli or placebo once in 2 weeks for 2 months. Sputum smear and culture examinations were performed at different time points. MIP was safe with no adverse effects. While sputum smear conversion did not show any statistically significant difference, significantly higher number of patients (67.1%) in the MIP group achieved sputum culture conversion at fourth week compared to the placebo (57%) group (p = 0.0002), suggesting a role of MIP in clearance of the bacilli. Since live bacteria are the major contributors for sustained incidence of TB, the potential of MIP in clearance of the bacilli has far reaching implications in controlling the spread of the disease.

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Shailendra Sachan

Papers

Detection of viable Mycobacterium leprae in soil samples: insights into possible sources of transmission of leprosy.

Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial

Predominance of three copies of tandem repeats in rpoT gene of Mycobacterium leprae from Northern India.