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Infection, Genetics and Evolution :... Dec 2020Molecular epidemiology investigations are notoriously challenging in the leprosy field mainly because the inherent characteristics of the disease as well as its yet... (Review)
Review
Molecular epidemiology investigations are notoriously challenging in the leprosy field mainly because the inherent characteristics of the disease as well as its yet uncultivated causative agents, Mycobacterium leprae and M. lepromatosis. Despite significant developments in understanding the biology of leprosy bacilli through genomic approaches, the exact mechanisms of transmission is still unclear and the factors underlying pathological variation of the disease in different patients remain as major gaps in our knowledge about leprosy. Despite these difficulties, the last two decades have seen the development of genotyping procedures based on PCR-sequencing of target loci as well as by the genome-wide analysis of an increasing number of geographically diverse isolates of leprosy bacilli. This has provided a foundation for molecular epidemiology studies that are bringing a better understanding of strain evolution associated with ancient human migrations, and phylogeographical insights about the spread of disease globally. This review discusses the advantages and drawbacks of the main tools available for molecular epidemiological investigations of leprosy and summarizes various methods ranging from PCR-based genotyping to genome-typing techniques. We also describe their main applications in analyzing the short-range and long-range transmission of the disease. Finally, we summarise the current gaps and challenges that remain in the field of molecular epidemiology of leprosy.
Topics: Genes, Bacterial; Genome, Bacterial; Genomics; Humans; Leprosy; Molecular Epidemiology; Mycobacterium leprae; Phylogeny; Public Health Surveillance
PubMed: 33022427
DOI: 10.1016/j.meegid.2020.104581 -
Future Microbiology Mar 2017Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant... (Review)
Review
Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant state. A change in lipid homeostasis upon infection is highly pronounced in Mycobacterium leprae. Lipids play an essential role in the survival and pathogenesis of mycobacteria. Lipids are present in several forms and serve multiple roles from being a source of nutrition, providing rigidity, evading the host immune response to serving as virulence factors, etc. The synthesis and degradation of lipids is a highly regulated process and is the key to future drug designing and diagnosis for mycobacteria. In the current review, an account of the distinct roles served by lipids, the mechanism of their synthesis and degradation has been elucidated.
Topics: Animals; Bacterial Proteins; Humans; Leprosy; Lipid Metabolism; Mycobacterium leprae; Virulence Factors
PubMed: 28287297
DOI: 10.2217/fmb-2016-0173 -
Frontiers in Cellular and Infection... 2021, the causative agent of leprosy, is an obligate intracellular pathogen primarily residing within host macrophages and Schwann cells. Whole genome sequencing predicts a...
, the causative agent of leprosy, is an obligate intracellular pathogen primarily residing within host macrophages and Schwann cells. Whole genome sequencing predicts a highly degraded genome with approximately one third of the coding capacity resulting in the loss of many catabolic pathways. Therefore, it can be assumed that obtains many of the necessary metabolites for intracellular survival and growth from the host cells. In this study, global transcriptomic analyses were done on freshly harvested growing in athymic mouse footpads for five months (MFP5) and compared to those held in axenic medium for 48 (ML48) and 96 (ML96) hours. Results show that all of the genes and pseudogenes were transcribed under both and conditions. 24% and 33% of gene transcript levels were significantly altered in ML48 and ML96 respectively, compared to MFP5. Approximately 45% (39/86) of lipid metabolism genes were significantly downregulated in ML96 compared to MFP5, majority of which are in the β-oxidation pathway. Cholesterol oxidase, acyl-CoA dehydrogenase, and coenzyme F420-dependent oxidoreductase, were significantly upregulated in both ML48 and ML96 compared to MFP5. 30% of cell wall and cell processes functional category genes had altered gene transcription at 96hr compared to MFP5. 40% of 57 genes associated with mycobacterial virulence showed significantly altered transcript levels with 52% significantly downregulated in ML96, including most of the Pro-Glu/Pro-Pro-Glu genes. All 111 hypothetical protein genes with unknown function were expressed. Adenosine triphosphate (ATP) synthesis in appears to be significantly downregulated under conditions. This is the first study comparing global gene expression during growth and stationery phase in axenic medium confirming that during the growth phase in the footpads of experimentally infected mice, is metabolically active and its primary source of energy production is probably lipids.
Topics: Animals; Gene Expression Profiling; Leprosy; Macrophages; Mice; Mycobacterium leprae; Transcriptome
PubMed: 35096659
DOI: 10.3389/fcimb.2021.817221 -
Biochemical Pharmacology Jul 2020Leprosy is a chronic infectious disease caused my Mycobacterium leprae that primarily affects peripheral nervous system and extremities and is prevalent in tropical... (Review)
Review
Leprosy is a chronic infectious disease caused my Mycobacterium leprae that primarily affects peripheral nervous system and extremities and is prevalent in tropical countries. Treatment for leprosy with multidrug regimens is very effective compared to monotherapy especially in multibacillary cases. The three major antileprosy drugs currently in use are 4, 4'-diaminodiphenyl sulfone (DDS, dapsone), rifampicin, and clofazimine. During multidrug therapy, the potent antibiotic rifampicin induces the metabolism of dapsone, which results in decreased plasma half-life of dapsone and its metabolites. Furthermore, rifampicin induces its own metabolism and decreases its half-life during monotherapy. Rifampicin upregulates several hepatic microsomal drug-metabolizing enzymes, especially cytochrome P450 (CYP) family that in turn induce the metabolism of dapsone. Clofazimine lacks significant induction of any drug-metabolizing enzyme including CYP family and does not interact with dapsone metabolism. Rifampicin does not induce clofazimine metabolism during combination treatment. Administration of dapsone in the acetylated form (acedapsone) can release the drug slowly into circulation up to 75 days and could be useful for the effective treatment of paucibacillary cases along with rifampicin. This review summarizes the major aspects of antileprosy drug metabolism and drug interactions and the role of cytochrome P450 family of drug metabolizing enzymes, especially CYP3A4 during multidrug regimens for the treatment of leprosy.
Topics: Acedapsone; Biological Availability; Biotransformation; Clofazimine; Cytochrome P-450 CYP3A; Dapsone; Drug Interactions; Drug Therapy, Combination; Half-Life; Humans; Leprostatic Agents; Leprosy; Metabolic Clearance Rate; Metabolic Networks and Pathways; Mycobacterium leprae; Rifampin
PubMed: 32339493
DOI: 10.1016/j.bcp.2020.113993 -
The American Journal of Tropical... Aug 2014
Topics: Aged, 80 and over; Clofazimine; Dapsone; Humans; Leprostatic Agents; Leprosy; Male; Mycobacterium leprae; Rifampin; Skin; Treatment Outcome
PubMed: 25100789
DOI: 10.4269/ajtmh.13-0668 -
Pathogens and Disease Aug 2018Leprosy is a chronic infectious disease caused by Mycobacterium leprae. This disease is characterized by skin and peripheral nerve trunk damage. The mechanisms... (Review)
Review
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. This disease is characterized by skin and peripheral nerve trunk damage. The mechanisms responsible for the observed nerve damage in leprosy could be directly related to the ability of M. leprae to infect Schwann cells, leading to triggering of signaling events. Therefore, we hypothesize that in response to M. leprae infection, activation of the Notch signaling pathway in Schwann cells could play a crucial role in glial cell dedifferentiation. On the other hand, nerve damage evidenced in this disease may be additionally explained by indirect mechanisms such as the immune response and genetic susceptibility of the host. The understanding of the mechanisms leading to nerve damage induced by M. leprae infection will allow us to generate valuable tools for the early detection of leprosy as well as for the mitigation of the effects of this disabling disease.
Topics: Humans; Leprosy; Mycobacterium leprae; Neuroglia; Peripheral Nerves; Receptors, Notch; Schwann Cells; Signal Transduction
PubMed: 30052986
DOI: 10.1093/femspd/fty062 -
Infectious Diseases of Poverty Nov 2020Leprosy control achieved dramatic success in the 1980s-1990s with the implementation of short course multidrug therapy, which reduced the global prevalence of leprosy to...
BACKGROUND
Leprosy control achieved dramatic success in the 1980s-1990s with the implementation of short course multidrug therapy, which reduced the global prevalence of leprosy to less than 1 in 10 000 population. However, a period of relative stagnation in leprosy control followed this achievement, and only limited further declines in the global number of new cases reported have been achieved over the past decade.
MAIN TEXT
In 2016, major stakeholders called for the development of an innovative and comprehensive leprosy strategy aimed at reducing the incidence of leprosy, lowering the burden of disability and discrimination, and interrupting transmission. This led to the establishment of the Global Partnership for Zero Leprosy (GPZL) in 2018, with partners aligned around a shared Action Framework committed to achieving the WHO targets by 2030 through national leprosy program capacity-building, resource mobilisation and an enabling research agenda. GPZL convened over 140 experts from more than 20 countries to develop a research agenda to achieve zero leprosy. The result is a detailed research agenda focusing on diagnostics, mapping, digital technology and innovation, disability, epidemiological modelling and investment case, implementation research, stigma, post exposure prophylaxis and transmission, and vaccines. This research agenda is aligned with the research priorities identified by other stakeholders.
CONCLUSIONS
Developing and achieving consensus on the research agenda for zero leprosy is a significant step forward for the leprosy community. In a next step, research programmes must be developed, with individual components of the research agenda requiring distinct expertise, varying in resource needs, and operating over different timescales. Moving toward zero leprosy now requires partner alignment and new investments at all stages of the research process, from discovery to implementation.
Topics: Bacterial Vaccines; Biomedical Research; Drug Therapy, Combination; Humans; Incidence; Leprostatic Agents; Leprosy; Mycobacterium leprae; Post-Exposure Prophylaxis; Research Design
PubMed: 33183339
DOI: 10.1186/s40249-020-00774-4 -
American Journal of Clinical Pathology Oct 2014To differentiate the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis and correlate them with geographic distribution and clinicopathologic features.
OBJECTIVES
To differentiate the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis and correlate them with geographic distribution and clinicopathologic features.
METHODS
Species-specific polymerase chain reactions were used to detect each bacillus in archived skin biopsy specimens from patients with leprosy from Brazil (n = 52), Malaysia (n = 31), Myanmar (n = 9), and Uganda (n = 4). Findings were correlated with clinical and pathologic data.
RESULTS
Etiologic species was detected in 46 of the 52 Brazilian patients, including 36 patients with M leprae, seven with M lepromatosis, and three with both bacilli. The seven patients with sole M lepromatosis all had tuberculoid leprosy, whereas only nine of the 36 patients infected with M leprae exhibited this type, and the rest were lepromatous (P < .001). All patients with dual infections had lepromatous leprosy. Of the nine patients from Myanmar, six were test positive: four with M leprae and two with M lepromatosis. Of the Malaysian and Ugandan patients, only M leprae was detected in 27 of the 31 Malaysians and two of the four Ugandans.
CONCLUSIONS
The leprosy agents vary in geographic distribution. Finding M lepromatosis in Brazil and Myanmar suggests wide existence of this newly discovered species. The leprosy manifestations likely vary with the etiologic agents.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brazil; Child; Child, Preschool; Coinfection; Diagnosis, Differential; Female; Humans; Leprosy; Leprosy, Lepromatous; Leprosy, Tuberculoid; Malaysia; Male; Middle Aged; Myanmar; Mycobacterium; Mycobacterium leprae; Species Specificity; Uganda; Young Adult
PubMed: 25239420
DOI: 10.1309/AJCP1GLCBE5CDZRM -
Current Topics in Medicinal Chemistry 2018Many of the tropical diseases are neglected by the researchers and medicinal companies due to lack of profit and other interests. The Drugs for Neglected Diseases... (Review)
Review
BACKGROUND
Many of the tropical diseases are neglected by the researchers and medicinal companies due to lack of profit and other interests. The Drugs for Neglected Diseases initiative (DNDi) is established to overcome the problems associated with these neglected diseases. According to a report published by the WHO, leprosy (Hansen's disease) is also a neglected infectious disease.
METHODS
A negligible amount of advancements has been made in last few decades which includes the tools of diagnosis, causes, treatment, and genetic studies of the bacterium (Mycobacterium leprae) that causes leprosy. The diagnosis of leprosy at earlier stages is important for its effective treatment. Recent studies on vitamin D and its receptors make leprosy diagnosis easier at earlier stages. Skin biopsies and qPCR are the other tools to identify the disease at its initial stages.
RESULTS
Until now a specific drug for the treatment of leprosy is not available, therefore, Multi-Drug Therapy (MDT) is used, which is hazardous to health. Besides Mycobacterium leprae, recently a new bacterium Mycobacterium lepromatosis was also identified as a cause of leprosy. During the last few years the genetic studies of Mycobacterium leprae, the role of vitamin D and vitamin D receptors (VDR), and the skin biopsies made the treatment and diagnosis of leprosy easier at early stages. The studies of micro RNAs (miRNAs) made it easy to differentiate leprosy from other diseases especially from tuberculosis.
CONCLUSION
Leprosy can be distinguished from sarcoidosis by quantitative study of reticulin fibers present in skin. The treatment used until now for leprosy is multi-drug treatment. The complete genome identification of Mycobacterium leprae makes the research easy to develop target specified drugs for leprosy. Rifampicin, identified as a potent drug, along with other drugs in uniform multi-drug treatment, has a significant effect when given to leprosy patients at initial stages. These are effective treatments but a specific drug for leprosy is still needed to be identified. The current review highlights the use of modern methods for the identification of leprosy at its earlier stages and the effective use of drugs alone as well as in combination.
Topics: Humans; Leprostatic Agents; Leprosy; Mycobacterium leprae
PubMed: 30360715
DOI: 10.2174/1568026618666181025100434 -
Microbiology Spectrum Jul 2019The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals.... (Review)
Review
The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals. Subsequent clinical manifestation is apparent with the impairment of the functional units of the nervous system, i.e., the neurons and the supporting glial cells that produce myelin sheaths around axons and provide trophic support to axons and neurons. Most of these neurotrophic bacteria display unique features, have coevolved with the functional sophistication of the nervous system cells, and have adapted remarkably to manipulate neural cell functions for their own advantage. Understanding how these bacterial pathogens establish intracellular adaptation by hijacking endogenous pathways in the nervous system, initiating myelin damage and axonal degeneration, and interfering with myelin maintenance provides new knowledge not only for developing strategies to combat neurodegenerative conditions induced by these pathogens but also for gaining novel insights into cellular and molecular pathways that regulate nervous system functions. Since the pathways hijacked by bacterial pathogens may also be associated with other neurodegenerative diseases, it is anticipated that detailing the mechanisms of bacterial manipulation of neural systems may shed light on common mechanisms, particularly of early disease events. This chapter details a classic example of neurodegeneration, that caused by , which primarily infects glial cells of the peripheral nervous system (Schwann cells), and how it targets and adapts intracellularly by reprogramming Schwann cells to stem cells/progenitor cells. We also discuss implications of this host cell reprogramming by leprosy bacilli as a model in a wider context.
Topics: Adaptation, Physiological; Animals; Humans; Leprosy; Mycobacterium leprae; Peripheral Nervous System; Schwann Cells
PubMed: 31322104
DOI: 10.1128/microbiolspec.BAI-0020-2019