Concept: Mycobacterium leprae
Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-β and its downstream genes, including interleukin 10 (IL-10), were induced in monocytes by M. leprae in vitro, and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-β and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.
Background “Tender cutaneous nodules of the legs” is a common manifestation in dermatology. Histopathological investigation is usually required for this condition, because clinical data are frequently insufficient to make a definite diagnosis. Objective To identify and analyze the causes of patients presenting with tender leg nodules and to reveal clinical clues that could help to differentiate causes. Materials and methods The medical records and histopathological slides of patients presenting with tender cutaneous nodules of the legs between January 2005 and December 2007 were retrospectively reviewed. Results Of the total of 154 patients, 122 (79.2%) were female. Definite diagnoses were categorized into four groups: inflammation (84.4%); infection (5.8%); tumor (6.5%); and nonspecific (3.2%). The most common cause in the inflammation group was erythema nodosum. The infections found were Acremonium spp., Penicillium sp., Mycobacterium abscessus, Mycobacterium fortuitum and Mycobacterium leprae. The tumors included leiomyoma, leukemia cutis, and lymphomas. Clinical data that correlated with and could be used as clues for the inflammation group were female sex (P = 0.03, OR 6.43) and lower leg involvement (P = 0.03, OR 7.14). Limitations The retrospective manner of this study is a limitation. Conclusion Various inflammatory conditions, infections, and tumors can present as tender cutaneous nodules of the legs. Female sex and lower leg involvement were clinical data that could be used as clues for the diagnoses in the inflammation group. However, histopathological investigation is still crucial to determine a definite diagnosis in patients presenting with tender cutaneous nodules of the legs.
Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae, contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis. From an evolutionary perspective, confirmation of our hypothesis may provide another example of heterozygote advantage.
Polymorphisms in innate immunity genes are known to be involved in the multifactorial susceptibility to Mycobacterium leprae infection. M. leprae can downregulate IL-1ß secretion escaping monocyte digestion. The intracellular receptors NLRPs (NACHT, LRR and PYD domains-containing proteins) sense pathogen associated molecular patterns (PAMPs) activating caspase-1 and IL-1ß secretion in the context of inflammasome. Considering the possible role of inflammasome in the immune response against M. leprae, known single nucleotide polymorphisms (SNPs) in two NLRP genes, NLRP1 and NLRP3, were analysed in Brazilian leprosy patients. Disease-associated SNPs (5 in NLRP1 and 2 in NLRP3), previously associated to infections and to immunologic disorders, were genotyped in 467 leprosy patients (327 multibacillary, MB; 96 paucibacillary, PB) and in 380 healthy controls (HC) from the state of Sao Paulo (Brazil), and in 183 patients (147 MB; 64 PB) and 186 HC from Mato Grosso (Brazil). Logistic regression analysis was performed considering susceptibility to leprosy di per se (leprosy versus HC) and clinical form (MB versus PB), adjusting for gender and ethnicity. Whereas none of the considered SNPs were statistically associated with leprosy, the NLRP1 combined haplotype rs2137722/G-rs12150220/T-rs2670660/G resulted significantly more frequent in patients than in HC as well as in PB than in MB. While both associations were lost after correction for gender and ethnicity, the NLRP1 combined haplotype rs2137722/G-rs12150220/A-rs2670660/G resulted strongly associated to PB. NLRP1 might be involved in the susceptibility to leprosy with particular emphasis for PB clinical form. Although preliminary, this is the first report linking NLRPs and inflammasome with leprosy: replication studies as well as functional assays are envisaged to deeper investigate the role of NLRP1 in M leprae infection. Interestingly, NLRP1 SNPs were previously associated to susceptibility to Crohn disease, suggesting that NLRP1 could be a new modifier gene in common between leprosy and Crohn disease.
Introduction: Despite the effectiveness of multidrug therapy, leprosy still represents a significant global health problem: transmission of Mycobacterium leprae (M. leprae) is not sufficiently reduced as witnessed by unwavering new case rates in leprosy-endemic countries. Early detection of M. leprae infection (before clinical manifestations occur) is vital to reduction of transmission. Current diagnosis relies on detection of clinical signs since there are no tests available to detect asymptomatic M. leprae infection or predict progression to leprosy. Areas covered: Identification of risk factors (immunological or genetic biomarkers) for disease development and/or onset of leprosy reactions is imperative for efficient diagnosis. Tests simultaneously detecting biomarkers specific for cellular and humoral immunity are well suited for diagnosis of different clinical outcomes of leprosy. This review describes the challenges of discovery of biomarkers for M. leprae infection and their implementation in field-friendly tests. Expert opinion: In view of the complicated nature of M. leprae infections, it is essential to invest in longitudinal studies allowing intra-individual comparison of immune and genetic biomarkers in various leprosy-endemic areas. Furthermore, the effect of co-infections on biomarker profiles should also be taken into account. Diagnostic tests based on such biomarkers can contribute significantly to early detection of leprosy (reactions) thus helping reduce nerve damage.
Lsr 2 protein of Mycobacterium leprae (ML) and its synthetic peptides were shown earlier to elicit lymphoproliferation and interferon γ (IFN γ) release by peripheral blood mononuclear cells (PBMC) of lepromatous leprosy patients (1). PBMC from 16 lepromatous patients undergoing erythema nodosum leprosum (ENL, Type 2) and 5 with reversal reactions (RR, Type 1) were stimulated with ML, recombinant Lsr 2 and six end to end synthetic peptides ( A-F) spanning the Lsr 2 sequence. During reaction all ENL patients showed lymphoproliferation (> 2 stimulation index) to peptides A and F with other peptides eliciting responses in 75-88% of the subjects. Both lymphoproliferation and IFN γ release for peptide E was significantly higher compared to peptides, B,C and recombinant Lsr 2 (p< 0.05, Wilcoxon signed rank test) in PBMC cultures. Five RR patients also showed enhanced lymphoproliferative responses and IFN γ release to Lsr 2, ML and peptide E. Six months post reaction, 14 ENL patients continued to exhibit responses to Lsr 2 and its peptides with the highest responses being elicited by peptide E. However, 5 subjects showed no lymphoproliferation and reduced IFN γ release to Lsr 2 peptides (p< 0.001, Kruskal Wallis test) but responded to recombinant Lsr 2. Six ENL patients had HLA A*68.01 which showed high peptide binding scores of 20-21 for peptides E, B, C using STFPEITHI program. Eleven patients had HLA-DRB1*1501 and *1502 which had high binding scores for peptides C and E. Thus, Lsr 2 and its peptides are recognized in leprosy reactions during and well after subsidence of clinical signs.
Leprosy is an endemic infectious disease caused by Mycobacterium leprae that predominantly attacks the skin and peripheral nerves, leading to progressive impairment of motor, sensory and autonomic function. Little is known about how this peripheral neuropathy affects corticospinal excitability of handgrip muscles. Our purpose was to explore the motor cortex organization after progressive peripheral nerve injury and upper-limb dysfunction induced by leprosy using noninvasive transcranial magnetic stimulation (TMS).
Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. Human leprosy has been documented for millennia in ancient cultures. Recent genomic studies of worldwide M. leprae strains have further traced it along global human dispersals during the past ∼100,000 years. Because leprosy bacilli are strictly intracellular, we wonder how long humans have been affected by this disease-causing parasite. Based on recently published data on M. leprae genomes, M. lepromatosis discovery, leprosy bacilli evolution, and human evolution, it is most likely that the leprosy bacilli started parasitic evolution in humans or early hominids millions of years ago. This makes leprosy the oldest human-specific infection. The unique adaptive evolution has likely molded the indolent growth and evasion from human immune defense that may explain leprosy pathogenesis. Accordingly, leprosy can be viewed as a natural consequence of a long parasitism. The burden of leprosy may have affected minor selection on human genetic polymorphisms.
HLA-B(∗)46:01 was formed by an intergenic mini-conversion, between HLA-B(∗)15:01 and HLA-C(∗)01:02, in Southeast Asia during the last 50,000 years, and it has since become the most common HLA-B allele in the region. A functional effect of the mini-conversion was introduction of the C1 epitope into HLA-B(∗)46:01, making it an exceptional HLA-B allotype that is recognized by the C1-specific natural killer (NK) cell receptor KIR2DL3. High-resolution mass spectrometry showed that HLA-B(∗)46:01 has a low-diversity peptidome that is distinct from those of its parents. A minority (21%) of HLA-B(∗)46:01 peptides, with common C-terminal characteristics, form ligands for KIR2DL3. The HLA-B(∗)46:01 peptidome is predicted to be enriched for peptide antigens derived from Mycobacterium leprae. Overall, the results indicate that the distinctive peptidome and functions of HLA-B(∗)46:01 provide carriers with resistance to leprosy, which drove its rapid rise in frequency in Southeast Asia.
Leprosy is a curable neglected disease of humans caused by Mycobacterium leprae that affects the skin and peripheral nerves and manifests clinically in various forms ranging from self-resolving, tuberculoid leprosy to lepromatous leprosy having significant pathology with ensuing disfiguration disability and social stigma. Despite the global success of multi-drug therapy (MDT), incidences of clinical leprosy have been observed in individuals with no apparent exposure to other cases, suggestive of possible non-human sources of the bacteria. In this study we show that common free-living amoebae (FLA) can phagocytose M. leprae, and allow the bacillus to remain viable for up to 8 months within amoebic cysts. Viable bacilli were extracted from separate encysted cocultures comprising three common Acanthamoeba spp.: A. lenticulata, A. castellanii, and A. polyphaga and two strains of Hartmannella vermiformis. Trophozoites of these common FLA take up M. leprae by phagocytosis. M. leprae from infected trophozoites induced to encyst for long-term storage of the bacilli emerged viable by assessment of membrane integrity. The majority (80%) of mice that were injected with bacilli extracted from 35 day cocultures of encysted/excysted A. castellanii and A. polyphaga showed lesion development that was similar to mice challenged with fresh M. leprae from passage mice albeit at a slower initial rate. Mice challenged with coculture-extracted bacilli showed evidence of acid-fast bacteria and positive PCR signal for M. leprae. These data support the conclusion that M. leprae can remain viable long-term in environmentally ubiquitous FLA and retain virulence as assessed in the nu/nu mouse model. Additionally, this work supports the idea that M. leprae might be sustained in the environment between hosts in FLA and such residence in FLA may provide a macrophage-like niche contributing to the higher-than-expected rate of leprosy transmission despite a significant decrease in human reservoirs due to MDT.