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Drug Discovery Today Jul 2021Hansen's disease (HD), or leprosy, continues to be endemic in many parts of the world. Although multidrug therapy (MDT) is successful in curing a large number of... (Review)
Review
Hansen's disease (HD), or leprosy, continues to be endemic in many parts of the world. Although multidrug therapy (MDT) is successful in curing a large number of patients, some of them abandon it because it is a long-term treatment. Therefore, identification of new drug targets in Mycobacterium leprae is considered of high importance. Here, we introduce an overview of in silico and in vitro studies that might be of help in this endeavor. The essentiality of M. leprae proteins is reviewed with discussion of flux balance analysis, gene expression, and knockout articles. Finally, druggability techniques are proposed for the validation of new M. leprae protein targets (see Fig. 1).
Topics: Animals; Bacterial Proteins; Computer Simulation; Drug Design; Gene Ontology; Humans; Leprostatic Agents; Leprosy; Mycobacterium leprae
PubMed: 33798649
DOI: 10.1016/j.drudis.2021.03.026 -
Emerging Infectious Diseases May 2022Leprosy is a granulomatous infection caused by infection with Mycobacterium leprae or M. lepromatosis. We evaluated skin biopsy and slit skin smear samples from 92...
Leprosy is a granulomatous infection caused by infection with Mycobacterium leprae or M. lepromatosis. We evaluated skin biopsy and slit skin smear samples from 92 leprosy patients in Colombia by quantitative PCR. Five (5.4%) patients tested positive for M. lepromatosis, providing evidence of the presence of this pathogen in Colombia.
Topics: Colombia; Humans; Leprosy; Mycobacterium; Mycobacterium leprae
PubMed: 35450566
DOI: 10.3201/eid2805.212015 -
Emerging Microbes & Infections 2019Of the more than 190 distinct species of Mycobacterium genus, many are economically and clinically important pathogens of humans or animals. Among those mycobacteria... (Review)
Review
Of the more than 190 distinct species of Mycobacterium genus, many are economically and clinically important pathogens of humans or animals. Among those mycobacteria that infect humans, three species namely Mycobacterium tuberculosis (causative agent of tuberculosis), Mycobacterium leprae (causative agent of leprosy) and Mycobacterium abscessus (causative agent of chronic pulmonary infections) pose concern to global public health. Although antibiotics have been successfully developed to combat each of these, the emergence of drug-resistant strains is an increasing challenge for treatment and drug discovery. Here we describe the impact of the rapid expansion of genome sequencing and genome/pathway annotations that have greatly improved the progress of structure-guided drug discovery. We focus on the applications of comparative genomics, metabolomics, evolutionary bioinformatics and structural proteomics to identify potential drug targets. The opportunities and challenges for the design of drugs for M. tuberculosis, M. leprae and M. abscessus to combat resistance are discussed.
Topics: Animals; Bacterial Proteins; Computational Biology; Drug Discovery; Drug Resistance, Bacterial; Genome, Bacterial; Humans; Molecular Sequence Annotation; Mycobacterium; Mycobacterium abscessus; Mycobacterium leprae; Mycobacterium tuberculosis; Protein Conformation; Proteomics; Sequence Analysis, DNA
PubMed: 30866765
DOI: 10.1080/22221751.2018.1561158 -
Microbes and Infection Nov 2017Our previous study has demonstrated that IL-10 may modulate both indoleamine 2,3-dioxygenase (IDO) and CD163 expression in lepromatous leprosy (LL) cells, favoring...
Our previous study has demonstrated that IL-10 may modulate both indoleamine 2,3-dioxygenase (IDO) and CD163 expression in lepromatous leprosy (LL) cells, favoring Mycobacterium leprae persistence through induction of regulatory pathways and iron storage. Here, we observed that in LL lesion cells there is an increase in the expression of proteins involved in iron metabolism such as hemoglobin (Hb), haptoglobin, heme oxygenase 1 and transferrin receptor 1 (TfR1) when compared to tuberculoid leprosy (BT) cells. We also found increased iron deposits and diminished expression of the iron exporter ferroportin 1 in LL lesion cells. Hemin, but not FeSO stimulation, was able to enhance M. leprae viability by a mechanism that involves IDO. Analysis of cell phenotype in lesions demonstrated a predominance of M2 markers in LL when compared with BT lesion cells. A positive correlation between CD163 and PPARG with the bacillary index (BI) was observed. In contrast, TNF, STAT1 and CSF2 presented a negative correlation with the BI. In summary, this study demonstrates that iron may regulate IDO expression by a mechanism that involves IL-10, which may contribute for the predominance of M2-like phenotype in LL lesions that favors the phagocytosis and maintenance of M. leprae in host cells.
Topics: Adult; Female; Humans; Immunoblotting; Immunoenzyme Techniques; Indoleamine-Pyrrole 2,3,-Dioxygenase; Iron; Leprosy, Lepromatous; Male; Middle Aged; Mycobacterium leprae; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 28684130
DOI: 10.1016/j.micinf.2017.06.006 -
PLoS Neglected Tropical Diseases Jan 2017Leprosy in Colombia is in a stage of post elimination-since 1997, prevalence of the disease is less than 1/10000. However, the incidence of leprosy has remained stable,...
Leprosy in Colombia is in a stage of post elimination-since 1997, prevalence of the disease is less than 1/10000. However, the incidence of leprosy has remained stable, with 400-500 new cases reported annually, with MB leprosy representing 70% of these case and 10% having grade 2 disability. Thus, leprosy transmission is still occurring, and household contacts (HHCs) of leprosy patients are a population at high risk of contracting and suffering from the effects of the disease during their lifetime. We performed a cross-sectional study with the aim of evaluating leprosy transmission within Family Groups (FGs) from four Colombian departments: Antioquia, Bolívar, Córdoba and Sucre. This study included 159 FGs formed by 543 HHCs; 45 FGs were monitored twice, first in 2003 and again in 2012. Migration, forced displacement by violence, loss of contact with the health center and the lack of an agreement to participate in the second monitoring were the primary reasons not all FGs were tested a second time. In each HHC, a clinical examination was performed, epidemiological data recorded, the bacillary index determined, DNA was isolated for M. leprae detection by nested PCR and IgM anti-phenolic glycolipid-I (PGL-I) titers were inspected. Further, DNA from M. leprae isolates were typed and compared among FGs. Twenty-two (4.1%) of the 543 HHCs had IgM anti-PGL-I positive antibody titers, indicating infection. Nasal swabs (NS) taken from 113 HHCs were tested by RLEP PCR; 18 (16%) were positive for M. leprae DNA and two new leprosy cases were detected among the HHCs. Of the confirmed HHCs with leprosy, it was possible to genotype the bacterial strains from both the index case and their HHCs. We found that the genotype of these two strains agreed at 9 markers, showing the individuals to be infected by the same strain, indicating familiar transmission. HHCs of leprosy patients not only are a high-risk population for M. leprae infection, they can act as M. leprae carriers and therefore serve as sources for transmission and infection. Our results confirm familiar leprosy transmission and suggest that follow-up of HHCs is a good strategy for early diagnosis of leprosy and to monitor its transmission.
Topics: Adolescent; Adult; Aged; Antibodies, Bacterial; Child; Child, Preschool; Colombia; Cross-Sectional Studies; Family Characteristics; Female; Humans; Infant; Leprosy; Male; Middle Aged; Mycobacterium leprae; Young Adult
PubMed: 28114411
DOI: 10.1371/journal.pntd.0005325 -
Clinical Microbiology Reviews Apr 2006Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in... (Review)
Review
Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. The second is a peripheral neuropathy that is initiated by the infection and the accompanying immunological events. The infection is curable but not preventable, and leprosy remains a major global health problem, especially in the developing world, publicity to the contrary notwithstanding. Mycobacterium leprae remains noncultivable, and for over a century leprosy has presented major challenges in the fields of microbiology, pathology, immunology, and genetics; it continues to do so today. This review focuses on recent advances in our understanding of M. leprae and the host response to it, especially concerning molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis. Advances in experimental models include studies in gene knockout mice and the development of molecular techniques to explore the armadillo model. In clinical studies, notable progress has been made concerning the immunology and immunopathology of leprosy, the genetics of human resistance, mechanisms of nerve injury, and chemotherapy. In nearly all of these areas, however, leprosy remains poorly understood compared to other major bacterial diseases.
Topics: Animals; Anti-Infective Agents; Bacterial Proteins; Bacterial Vaccines; Disease Models, Animal; Disease Susceptibility; Drug Resistance, Bacterial; Genes, Bacterial; Genetic Predisposition to Disease; Genome, Bacterial; Humans; Immunity, Cellular; Immunity, Innate; Leprostatic Agents; Leprosy; Mice; Mycobacterium leprae; Peripheral Nerves; Peripheral Nervous System Diseases; Polymerase Chain Reaction; Schwann Cells
PubMed: 16614253
DOI: 10.1128/CMR.19.2.338-381.2006 -
BMC Infectious Diseases Jun 2019Leprosy is is still considered a public health issue and in Colombia 7-10% of new cases are found in children, indicating both active transmission and social inequality....
BACKGROUND
Leprosy is is still considered a public health issue and in Colombia 7-10% of new cases are found in children, indicating both active transmission and social inequality. We hypothesized that circulating antibodies against Natural Octyl Disaccharide-Leprosy IDRI Diagnostic (NDO-LID) (a combination of Mycobacterium leprae antigens) could reveal the social and environmental aspects associated with higher frequencies of M. leprae infection among children and adolescents in Colombia.
METHODS
An observational cross-sectional study was conducted involving sampling from 82 children and adolescents (younger than 18 years of age) who had household contact with index leprosy patients diagnosed in the last 5 years. Data were analyzed through bivariate analysis made by applying a Pearson x test for qualitative variables, while quantitative variables, depending on their distribution, were analyzed using either a Student's t-test or Mann-Whitney U test. Multivariate analysis was performed using a multiple regression and binomial logistic approach.
RESULTS
A bivariate analysis demonstrated that antibody titers against NDO-LID were significantly greater in children and adolescents with a low socioeconomic status that had: lived in vulnerable areas of the UAChR shared region; eaten armadillo meat; exposure of over 10 years to an index case and; not received BCG immunization. Moreover, a multivariate analysis showed that residing in the UAChR region has a strong association with a greater possibility of M. leprae infection.
CONCLUSIONS
M. leprae transmission persists among young Colombians, and this is associated with social and environmental conditions. An intensification of efforts to identify new leprosy cases in vulnerable and forgotten populations where M. leprae transmission continues therefore appears necessary.
Topics: Adolescent; Animals; Antibodies, Bacterial; Armadillos; BCG Vaccine; Child; Child, Preschool; Colombia; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Leprosy; Logistic Models; Male; Meat; Mycobacterium leprae; Social Class; Statistics, Nonparametric
PubMed: 31196008
DOI: 10.1186/s12879-019-4120-2 -
The Brazilian Journal of Infectious... 2017Leprosy, whose etiological agent is Mycobacterium leprae, is a chronic infectious disease that mainly affects the skin and peripheral nervous system. The diagnosis of...
Leprosy, whose etiological agent is Mycobacterium leprae, is a chronic infectious disease that mainly affects the skin and peripheral nervous system. The diagnosis of leprosy is based on clinical evaluation, whereas histopathological analysis and bacilloscopy are complementary diagnostic tools. Quantitative PCR (qPCR), a current useful tool for diagnosis of infectious diseases, has been used to detect several pathogens including Mycobacterium leprae. The validation of this technique in a robust set of samples comprising the different clinical forms of leprosy is still necessary. Thus, in this study samples from 126 skin biopsies (collected from patients on all clinical forms and reactional states of leprosy) and 25 slit skin smear of leprosy patients were comparatively analyzed by qPCR (performed with primers for the RLEP region of M. leprae DNA) and routine bacilloscopy performed in histological sections or in slit skin smear. Considering clinical diagnostic as the gold standard, 84.9% of the leprosy patients were qPCR positive in skin biopsies, resulting in 84.92% sensitivity, with 84.92 and 61.22% positive (PPV) and negative (NPV) predictive values, respectively. Concerning bacilloscopy of histological sections (BI/H), the sensitivity was 80.15% and the PPV and NPV were 80.15 and 44.44%, respectively. The concordance between qPCR and BI/H was 87.30%. Regarding the slit skin smear, 84% of the samples tested positive in the qPCR. Additionally, qPCR showed 100% specificity, since all samples from different mycobacteria, from healthy individuals, and from other granulomatous diseases presented negative results. In conclusion, the qPCR technique for detection of M. leprae using RLEP primers proved to be specific and sensitive, and qPCR can be used as a complementary test to diagnose leprosy irrespective of the clinical form of disease.
Topics: Biopsy; DNA Primers; DNA, Bacterial; Humans; Leprosy; Mycobacterium leprae; Real-Time Polymerase Chain Reaction; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Skin
PubMed: 27888674
DOI: 10.1016/j.bjid.2016.09.017 -
Memorias Do Instituto Oswaldo Cruz Dec 2012Human beings are the main reservoir of the causative agent of leprosy, Mycobacterium leprae. In the Americas, nine-banded armadillos (Dasypus novemcinctus) also act as a...
Human beings are the main reservoir of the causative agent of leprosy, Mycobacterium leprae. In the Americas, nine-banded armadillos (Dasypus novemcinctus) also act as a reservoir for the bacillus. In the state of Ceará (CE), which is located in Northeast Brazil and is an endemic area of leprosy, there are several species of armadillos, including D. novemcinctus and Euphractus sexcinctus (six-banded armadillo). Contact between humans and armadillos occur mainly through hunting, cleaning, preparing, cooking and eating. This study identified M. leprae DNA in the two main species of armadillos found in Northeast Brazil. A total of 29 wild armadillos (27 D. novemcinctus and 2 E. sexcinctus) were captured in different environments of CE countryside. Samples from the ear, nose, liver and spleen from each of these animals were tested by a nested M. leprae-specific repetitive element polymerase chain reaction assay. The samples that tested positive were confirmed by DNA sequencing. M. leprae was detected in 21% (6/29) of the animals, including five D. novemcinctus and one E. sexcinctus. This is the first Brazilian study to identify the presence of a biomarker of M. leprae in wild armadillos (D. novemcinctus and E. sexcinctus) in a leprosy hyperendemic area where there is continuous contact between humans and armadillos.
Topics: Animals; Animals, Wild; Armadillos; DNA, Bacterial; Disease Reservoirs; Female; Male; Mycobacterium leprae; Polymerase Chain Reaction
PubMed: 23283473
DOI: 10.1590/s0074-02762012000900029 -
Journal of Bacteriology Oct 2009Mycobacterium lepromatosis is a newly discovered leprosy-causing organism. Preliminary phylogenetic analysis of its 16S rRNA gene and a few other gene segments revealed...
Mycobacterium lepromatosis is a newly discovered leprosy-causing organism. Preliminary phylogenetic analysis of its 16S rRNA gene and a few other gene segments revealed significant divergence from Mycobacterium leprae, a well-known cause of leprosy, that justifies the status of M. lepromatosis as a new species. In this study we analyzed the sequences of 20 genes and pseudogenes (22,814 nucleotides). Overall, the level of matching of these sequences with M. leprae sequences was 90.9%, which substantiated the species-level difference; the levels of matching for the 16S rRNA genes and 14 protein-encoding genes were 98.0% and 93.1%, respectively, but the level of matching for five pseudogenes was only 79.1%. Five conserved protein-encoding genes were selected to construct phylogenetic trees and to calculate the numbers of synonymous substitutions (dS values) and nonsynonymous substitutions (dN values) in the two species. Robust phylogenetic trees constructed using concatenated alignment of these genes placed M. lepromatosis and M. leprae in a tight cluster with long terminal branches, implying that the divergence occurred long ago. The dS and dN values were also much higher than those for other closest pairs of mycobacteria. The dS values were 14 to 28% of the dS values for M. leprae and Mycobacterium tuberculosis, a more divergent pair of species. These results thus indicate that M. lepromatosis and M. leprae diverged approximately 10 million years ago. The M. lepromatosis pseudogenes analyzed that were also pseudogenes in M. leprae showed nearly neutral evolution, and their relative ages were similar to those of M. leprae pseudogenes, suggesting that they were pseudogenes before divergence. Taken together, the results described above indicate that M. lepromatosis and M. leprae diverged from a common ancestor after the massive gene inactivation event described previously for M. leprae.
Topics: Bacterial Proteins; Base Composition; Leprosy; Likelihood Functions; Molecular Sequence Data; Mycobacterium; Mycobacterium leprae; Phylogeny; Polymerase Chain Reaction; Pseudogenes; RNA, Ribosomal, 16S; Sequence Analysis, DNA
PubMed: 19633074
DOI: 10.1128/JB.00762-09