Project description:Mineralised dental plaque (calculus) has proven to be an excellent source of ancient biomolecules. In this study we present a Mycobacterium leprae genome (6.6-fold), the causative agent of leprosy, recovered via shotgun sequencing of 16th century human dental calculus from an individual from Trondheim, Norway. Moreover, ancient mycobacterial peptides were retrieved via mass spectrometry-based proteomics, further validating the presence of the pathogen. M. leprae can readily be detected in the oral cavity and associated mucosal membranes, which likely contributed to it being incorporated into this individual’s dental calculus. This individual showed some possible, but not definitive, evidence of skeletal lesions associated with early stage leprosy. This study is the first known example of successful multi-omics retrieval of M. leprae from archaeological dental calculus. Furthermore, we offer new insights into dental calculus as an alternative sample source to bones or teeth for detecting and molecularly characterizing M. leprae in individuals from the archaeological record.
Project description:Mycobacterium leprae, the causative agent of leprosy, an obligate intracellular pathogen has the ability to survive and grow for extended periods within phagocytes and Schwann cells. M. leprae genome analysis predicts a highly degraded genome resulting in a significant loss of its genomic coding capacity. Detailed dynamics of carbon sources for energy utilization and growth of M. leprae is unclear. This study, therefore, presents M. leprae transcriptome during in vivo growth and ex vivo stationary phases, and explores metabolic pathways relevant to its growth from global gene expression data. This report provides a glimpse of some of M. leprae nutritional requirements for growth, which most likely, needs to be supplemented, in an axenic growth media.
Project description:8 leprosy patients including 4 multibacillary (MB) and 4 paucibacillary (PB), and 8 non-leprosy controls including 4 healthy house contacts (HHCs) and 4 endemic controls (ECs) were included in the study. The immune response differences between leprosy patients and controls were evaluated by analyzing the transcriptional profiles of PBMCs to M. leprae sonicate antigens by RNA-seq. The analyses revealed potential biomarkers (including mRNAs and lncRNAs) preferentially expressed in PBMCs in leprosy patients that may be useful for early diagnosis of leprosy.
Project description:Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation –– before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate, and thus likely between the human host and M. leprae bacilli. We found that reQTL are significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, as well as SNPs targeted by recent positive selection. Our study suggests that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection.
Project description:To this date, host transcriptome studies in leprosy have focused on Schwann cells, as well as mouse-footpad and skin biopsies. Despite macrophages being the most infected cell types in leprosy lesions, there is no genome-wide experiments with this model. Here, we aimed at identifying host macrophages transcriptional changes induced by live-Mycobacterium leprae infection for 48 hours.