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The National Medical Journal of India 1994
Topics: BCG Vaccine; Bacterial Vaccines; Humans; Leprosy; Mycobacterium leprae; Vaccines, Inactivated
PubMed: 7950943
DOI: No ID Found -
Journal of Neurochemistry Jan 2023Leprosy is a chronic infectious disease caused by Mycobacterium leprae infection in Schwann cells. Axonopathy is considered a hallmark of leprosy neuropathy and is...
Leprosy is a chronic infectious disease caused by Mycobacterium leprae infection in Schwann cells. Axonopathy is considered a hallmark of leprosy neuropathy and is associated with the irreversible motor and sensory loss seen in infected patients. Although M. leprae is recognized to provoke Schwann cell dedifferentiation, the mechanisms involved in the contribution of this phenomenon to neural damage remain unclear. In the present work, we used live M. leprae to infect the immortalized human Schwann cell line ST8814. The neurotoxicity of infected Schwann cell-conditioned medium (SCCM) was then evaluated in a human neuroblastoma cell lineage and mouse neurons. ST8814 Schwann cells exposed to M. leprae affected neuronal viability by deviating glial C-labeled lactate, important fuel of neuronal central metabolism, to de novo lipid synthesis. The phenolic glycolipid-1 (PGL-1) is a specific M. leprae cell wall antigen proposed to mediate bacterial-Schwann cell interaction. Therefore, we assessed the role of the PGL-1 on Schwann cell phenotype by using transgenic M. bovis (BCG)-expressing the M. leprae PGL-1. We observed that BCG-PGL-1 was able to induce a phenotype similar to M. leprae, unlike the wild-type BCG strain. We next demonstrated that this Schwann cell neurotoxic phenotype, induced by M. leprae PGL-1, occurs through the protein kinase B (Akt) pathway. Interestingly, the pharmacological inhibition of Akt by triciribine significantly reduced free fatty acid content in the SCCM from M. leprae- and BCG-PGL-1-infected Schwann cells and, hence, preventing neuronal death. Overall, these findings provide novel evidence that both M. leprae and PGL-1, induce a toxic Schwann cell phenotype, by modifying the host lipid metabolism, resulting in profound implications for neuronal loss. We consider this metabolic rewiring a new molecular mechanism to be the basis of leprosy neuropathy.
Topics: Humans; Animals; Mice; Mycobacterium leprae; Proto-Oncogene Proteins c-akt; Glycolipids; BCG Vaccine; Leprosy; Schwann Cells
PubMed: 36349509
DOI: 10.1111/jnc.15722 -
The Indian Journal of Medical Research Jan 2019
Topics: Humans; Leprosy; Mycobacterium leprae; Post-Exposure Prophylaxis; Vaccines
PubMed: 31115367
DOI: 10.4103/ijmr.IJMR_12_19 -
Scientific Reports Feb 2019Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin and nerves. Despite decades of availability of adequate treatment, transmission is...
Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin and nerves. Despite decades of availability of adequate treatment, transmission is unabated and transmission routes are not completely understood. Despite the general assumption that untreated M. leprae infected humans represent the major source of transmission, scarce reports indicate that environmental sources could also play a role as a reservoir. We investigated whether M. leprae DNA is present in soil of regions where leprosy is endemic or areas with possible animal reservoirs (armadillos and red squirrels). Soil samples (n = 73) were collected in Bangladesh, Suriname and the British Isles. Presence of M. leprae DNA was determined by RLEP PCR and genotypes were further identified by Sanger sequencing. M. leprae DNA was identified in 16.0% of soil from houses of leprosy patients (Bangladesh), in 10.7% from armadillos' holes (Suriname) and in 5% from the habitat of lepromatous red squirrels (British Isles). Genotype 1 was found in Bangladesh whilst in Suriname the genotype was 1 or 2. M. leprae DNA can be detected in soil near human and animal sources, suggesting that environmental sources represent (temporary) reservoirs for M. leprae.
Topics: Animals; Bangladesh; Ecosystem; Genotype; Humans; Leprosy; Mycobacterium leprae; RNA, Ribosomal, 16S; Soil Microbiology; Suriname
PubMed: 30816338
DOI: 10.1038/s41598-019-39746-6 -
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 -
PloS One 2017Nitazoxanide (NTZ) is an anti-parasitic drug that also has activity against bacteria, including Mycobacterium tuberculosis. Our data using both radiorespirometry and...
Nitazoxanide (NTZ) is an anti-parasitic drug that also has activity against bacteria, including Mycobacterium tuberculosis. Our data using both radiorespirometry and live-dead staining in vitro demonstrate that NTZ similarly has bactericidal against M. leprae. Further, gavage of M. leprae-infected mice with NTZ at 25mg/kg provided anti-mycobacterial activity equivalent to rifampicin (RIF) at 10 mg/kg. This suggests that NTZ could be considered for leprosy treatment.
Topics: Animals; Anti-Bacterial Agents; Leprosy; Mice; Microbial Sensitivity Tests; Mycobacterium leprae; Nitro Compounds; Thiazoles
PubMed: 28850614
DOI: 10.1371/journal.pone.0184107 -
Infection and Immunity Jul 2013This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating...
This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that M. leprae can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of M. leprae to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important M. leprae entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived M. leprae cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins. In vitro assays with the recombinant forms of the histone-like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for M. leprae in humans. Moreover, our report sheds light on the potentially critical adhesins involved in M. leprae-epithelial cell interaction that may be useful in designing more effective tools for leprosy control.
Topics: Adhesins, Bacterial; Animals; Bacterial Adhesion; Bacterial Proteins; Cell Line, Tumor; Cytoskeleton; Epithelial Cells; Host-Pathogen Interactions; Humans; Leprosy; Mass Spectrometry; Mice; Mice, Inbred C57BL; Microbial Viability; Microscopy, Electron, Transmission; Mycobacterium leprae; Phagocytosis; Proteome; Pulmonary Alveoli; Recombinant Proteins
PubMed: 23670556
DOI: 10.1128/IAI.00147-13 -
Antimicrobial Agents and Chemotherapy May 2007Mycobacterium leprae, the causative agent of leprosy, is noncultivable in vitro; therefore, evaluation of antibiotic activity against M. leprae relies mainly upon the...
Mycobacterium leprae, the causative agent of leprosy, is noncultivable in vitro; therefore, evaluation of antibiotic activity against M. leprae relies mainly upon the mouse footpad system, which requires at least 12 months before the results become available. We have developed an in vitro assay for studying the activities of quinolones against the DNA gyrase of M. leprae. We overexpressed in Escherichia coli the M. leprae GyrA and GyrB subunits separately as His-tagged proteins by using a pET plasmid carrying the gyrA and gyrB genes. The soluble 97.5-kDa GyrA and 74.5-kDa GyrB subunits were purified by nickel chelate chromatography and were reconstituted as an enzyme with DNA supercoiling activity. Based on the drug concentrations that inhibited DNA supercoiling by 50% or that induced DNA cleavage by 25%, the 13 quinolones tested clustered into three groups. Analysis of the quinolone structure-activity relationship demonstrates that the most active quinolones against M. leprae DNA gyrase share the following structural features: a substituted carbon at position 8, a cyclopropyl substituent at N-1, a fluorine at C-6, and a substituent ring at C-7. We conclude that the assays based on DNA supercoiling inhibition and drug-induced DNA cleavage on purified M. leprae DNA gyrase are rapid, efficient, and safe methods for the screening of quinolone derivatives with potential in vivo activities against M. leprae.
Topics: Anti-Infective Agents; DNA; DNA Gyrase; DNA, Superhelical; Enzyme Inhibitors; Mycobacterium leprae; Quinolones; Topoisomerase II Inhibitors
PubMed: 17325221
DOI: 10.1128/AAC.01282-06 -
Infection and Immunity Feb 1990Intradermal (i.d.) immunization of Lewis rats with autoclaved Mycobacterium leprae resulted in antigen-specific proliferation responses and interleukin-2 release from...
Intradermal (i.d.) immunization of Lewis rats with autoclaved Mycobacterium leprae resulted in antigen-specific proliferation responses and interleukin-2 release from spleen and lymph node cells that were detectable as early as 21 days, persisted for at least 9 months, and were dependent on the dose of antigen administered. Immunized animals were also completely resistant to a footpad challenge with viable M. leprae. In contrast, intravenous (i.v.) administration of at least 10(8) irradiated M. leprae isolates induced a state of nonresponsiveness characterized by the absence of proliferation and interleukin-2 release by antigen-stimulated lymphoid cell cultures; however, in vitro responses to mitogenic stimulation and in vivo responses to keyhole limpet hemocyanin and Listeria monocytogenes were normal. Animals that received an i.v. injection of M. leprae remained nonresponsive to M. leprae antigens even after a subsequent i.d. immunization. This state of nonresponsiveness persisted for at least 6 months after induction. Results of footpad challenge experiments showed that the ability of animals rendered nonresponsive by an i.v. injection of M. leprae to control the growth of viable M. leprae in the footpad was not different from that of untreated rats. In addition, animals receiving an initial i.v. injection and a subsequent i.d. immunization with M. leprae were not protected from a viable challenge, as were rats that received only i.d. immunization. These results suggest that i.v. administration of a large dose of M. leprae to rats induces a state of nonresponsiveness to M. leprae antigens that may be similar to that seen in lepromatous leprosy patients.
Topics: Animals; Antigens, Bacterial; Immune Tolerance; Immunity, Cellular; Immunization; Interleukin-2; Leprosy; Lymphocyte Activation; Male; Mycobacterium leprae; Rats; Rats, Inbred Lew
PubMed: 2404873
DOI: 10.1128/iai.58.2.495-501.1990 -
Nihon Hansenbyo Gakkai Zasshi =... Feb 2009Completion of Mycobacterium leprae genome sequence revealed that there are many pseudogenes and non-coding regions, but rather small numbers of protein-coding genes.... (Review)
Review
Completion of Mycobacterium leprae genome sequence revealed that there are many pseudogenes and non-coding regions, but rather small numbers of protein-coding genes. This result indicates that M. leprae is a very unique organism, and this future is important to understand the biological nature and/or pathogenicity of M. leprae, which remain unclear. We attempted to find the biological nature of M. leprae by detecting the gene and pseudogene regions transcribed at high level. We detected the genomic regions including pseudogenes and demonstrated that six out of twelve high expression regions were pseudogenes. In addition, its transcription level was changed when M. leprae infects macrophage. RNA was detected from genes, pseudogenes and non-coding regions. The expression levels of these regions were different among patients and a part of them is disappeared just after treatment. These results suggested that RNA derived from pseudogene and non-coding region have some function concerning the infection and/or intracellular parasitism and that the analysis of pseudogene and non-coding region expression pattern of M. leprae is available as a criterion for therapeutic effect and disease type of leprosy, and a prognostic marker.
Topics: Gene Expression; Genome, Bacterial; Humans; Mycobacterium leprae; Oligonucleotide Array Sequence Analysis; Pseudogenes; RNA, Bacterial; Transcription, Genetic
PubMed: 19227151
DOI: 10.5025/hansen.78.61