Leprosy piRnome: exploring new possibilities for an old disease.

Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.

Myelin breakdown favours Mycobacterium leprae survival in Schwann cells.

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.

Myelin breakdown favours Mycobacterium leprae survival in Scwann cells

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.

Intracellular Mycobacterium leprae Utilizes Host Glucose as a Carbon Source in Schwann Cells.

New approaches are needed to control leprosy, but understanding of the biology of the causative agent Mycobacterium leprae remains rudimentary, principally because the pathogen cannot be grown in axenic culture. Here, we applied 13C isotopomer analysis to measure carbon metabolism of M. leprae in its primary host cell, the Schwann cell. We compared the results of this analysis with those of a related pathogen, Mycobacterium tuberculosis, growing in its primary host cell, the macrophage. Using 13C isotopomer analysis with glucose as the tracer, we show that whereas M. tuberculosis imports most of its amino acids directly from the host macrophage, M. leprae utilizes host glucose pools as the carbon source to biosynthesize the majority of its amino acids. Our analysis highlights the anaplerotic enzyme phosphoenolpyruvate carboxylase required for this intracellular diet of M. leprae, identifying this enzyme as a potential antileprosy drug target.IMPORTANCE Leprosy remains a major problem in the world today, particularly affecting the poorest and most disadvantaged sections of society in the least developed countries of the world. The long-term aim of research is to develop new treatments and vaccines, and these aims are currently hampered by our inability to grow the pathogen in axenic culture. In this study, we probed the metabolism of M. leprae while it is surviving and replicating inside its primary host cell, the Schwann cell, and compared it to a related pathogen, M. tuberculosis, replicating in macrophages. Our analysis revealed that unlike M. tuberculosis, M. leprae utilized host glucose as a carbon source and that it biosynthesized its own amino acids, rather than importing them from its host cell. We demonstrated that the enzyme phosphoenolpyruvate carboxylase plays a crucial role in glucose catabolism in M. leprae Our findings provide the first metabolic signature of M. leprae in the host Schwann cell and identify novel avenues for the development of antileprosy drugs.

Cell Biology of Intracellular Adaptation of Mycobacterium leprae in the Peripheral Nervous System.

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 Mycobacterium leprae, 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.

Myelination key factor krox-20 is downregulated in Schwann cells and murine sciatic nerves infected by Mycobacterium leprae.

Schwann cells (SCs) critically maintain the plasticity of the peripheral nervous system. Peripheral nerve injuries and infections stimulate SCs in order to retrieve homeostasis in neural tissues. Previous studies indicate that Mycobacterium leprae (ML) regulates the expression of key factors related to SC identity, suggesting that alterations in cell phenotype may be involved in the pathogenesis of neural damage in leprosy. To better understand whether ML restricts the plasticity of peripheral nerves, the present study sought to determine the expression of Krox-20, Sox-10, c-Jun and p75NTR in SC culture and mice sciatic nerves, both infected by ML Thai-53 strain. Primary SC cultures were stimulated with two different multiplicities of infection (MOI 100:1; MOI 50:1) and assessed after 7 and 14 days. Sciatic nerves of nude mice (NU-Foxn1nu ) infected with ML were evaluated after 6 and 9 months. In vitro results demonstrate downregulation of Krox-20 and Sox-10 along with the increase in p75NTR-immunolabelled cells. Concurrently, sciatic nerves of infected mice showed a significant decrease in Krox-20 and increase in p75NTR. Our results corroborate previous findings on the interference of ML in the expression of factors involved in cell maturation, favouring the maintenance of a non-myelinating phenotype in SCs, with possible implications for the repair of adult peripheral nerves.

Myelination key factor krox­20 is downregulated in Schwann cells and murine sciatic nerves infected by Mycobacterium leprae

Schwann cells (SCs) critically maintain the plasticity of the peripheral nervous system. Peripheral nerve injuries and infections stimulate SCs in order to retrieve homeostasis in neural tissues. Previous studies indicate that Mycobacterium leprae (ML) regulates the expression of key factors related to SC identity, suggesting that alterations in cell phenotype may be involved in the pathogenesis of neural damage in leprosy. To better understand whether ML restricts the plasticity of peripheral nerves, the present study sought to determine the expression of Krox­20, Sox­10, c­Jun and p75NTR in SC culture and mice sciatic nerves, both infected by ML Thai­53 strain. Primary SC cultures were stimulated with two different multiplicities of infection (MOI 100:1; MOI 50:1) and assessed after 7 and 14 days. Sciatic nerves of nude mice (NU­Foxn1nu) infected with ML were evaluated after 6 and 9 months. In vitro results demonstrate downregulation of Krox­20 and Sox­10 along with the increase in p75NTR­immunolabelled cells. Concurrently, sciatic nerves of infected mice showed a significant decrease in Krox­20 and increase in p75NTR. Our results corroborate previous findings on the interference of ML in the expression of factors involved in cell maturation, favouring the maintenance of a non­myelinating phenotype in SCs, with possible implications for the repair of adult peripheral nerves(AU).

Mycobacterium leprae-induced nerve damage: direct and indirect mechanisms.

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.

The formation of lipid droplets favors intracellular Mycobacterium leprae survival in SW-10, non-myelinating Schwann cells.

Leprosy is a chronic infectious disease that is caused by the obligate intracellular pathogen Mycobacterium leprae (M.leprae), which is the leading cause of all non-traumatic peripheral neuropathies worldwide. Although both myelinating and non-myelinating Schwann cells are infected by M.leprae in patients with lepromatous leprosy, M.leprae preferentially invades the non-myelinating Schwann cells. However, the effect of M.leprae infection on non-myelinating Schwann cells has not been elucidated. Lipid droplets (LDs) are found in M.leprae-infected Schwann cells in the nerve biopsies of lepromatous leprosy patients. M.leprae-induced LD formation favors intracellular M.leprae survival in primary Schwann cells and in a myelinating Schwann cell line referred to as ST88-14. In the current study, we initially characterized SW-10 cells and investigated the effects of LDs on M.leprae-infected SW-10 cells, which are non-myelinating Schwann cells. SW-10 cells express S100, a marker for cells from the neural crest, and NGFR p75, a marker for immature or non-myelinating Schwann cells. SW-10 cells, however, do not express myelin basic protein (MBP), a marker for myelinating Schwann cells, and myelin protein zero (MPZ), a marker for precursor, immature, or myelinating Schwann cells, all of which suggests that SW-10 cells are non-myelinating Schwann cells. In addition, SW-10 cells have phagocytic activity and can be infected with M. leprae. Infection with M. leprae induces the formation of LDs. Furthermore, inhibiting the formation of M. leprae-induced LD enhances the maturation of phagosomes containing live M.leprae and decreases the ATP content in the M. leprae found in SW-10 cells. These facts suggest that LD formation by M. leprae favors intracellular M. leprae survival in SW-10 cells, which leads to the logical conclusion that M.leprae-infected SW-10 cells can be a new model for investigating the interaction of M.leprae with non-myelinating Schwann cells.

Pathogenic mechanisms of intracellular bacteria.

PURPOSE OF REVIEW: We wished to overview recent data on a subset of epigenetic changes elicited by intracellular bacteria in human cells. Reprogramming the gene expression pattern of various host cells may facilitate bacterial growth, survival, and spread. RECENT FINDINGS: DNA-(cytosine C5)-methyltransferases of Mycoplasma hyorhinis targeting cytosine-phosphate-guanine (CpG) dinucleotides and a Mycobacterium tuberculosis methyltransferase targeting non-CpG sites methylated the host cell DNA and altered the pattern of gene expression. Gene silencing by CpG methylation and histone deacetylation, mediated by cellular enzymes, also occurred in M. tuberculosis-infected macrophages. M. tuberculosis elicited cell type-specific epigenetic changes: it caused increased DNA methylation in macrophages, but induced demethylation, deposition of euchromatic histone marks and activation of immune-related genes in dendritic cells. A secreted transposase of Acinetobacter baumannii silenced a cellular gene, whereas Mycobacterium leprae altered the epigenotype, phenotype, and fate of infected Schwann cells. The 'keystone pathogen' oral bacterium Porphyromonas gingivalis induced local DNA methylation and increased the level of histone acetylation in host cells. These epigenetic changes at the biofilm-gingiva interface may contribute to the development of periodontitis. SUMMARY: Epigenetic regulators produced by intracellular bacteria alter the epigenotype and gene expression pattern of host cells and play an important role in pathogenesis.

Subversion of Schwann Cell Glucose Metabolism by Mycobacterium leprae.

Mycobacterium leprae, the intracellular etiological agent of leprosy, infects Schwann promoting irreversible physical disabilities and deformities. These cells are responsible for myelination and maintenance of axonal energy metabolism through export of metabolites, such as lactate and pyruvate. In the present work, we observed that infected Schwann cells increase glucose uptake with a concomitant increase in glucose-6-phosphate dehydrogenase (G6PDH) activity, the key enzyme of the oxidative pentose pathway. We also observed a mitochondria shutdown in infected cells and mitochondrial swelling in pure neural leprosy nerves. The classic Warburg effect described in macrophages infected by Mycobacterium avium was not observed in our model, which presented a drastic reduction in lactate generation and release by infected Schwann cells. This effect was followed by a decrease in lactate dehydrogenase isoform M (LDH-M) activity and an increase in cellular protection against hydrogen peroxide insult in a pentose phosphate pathway and GSH-dependent manner. M. leprae infection success was also dependent of the glutathione antioxidant system and its main reducing power source, the pentose pathway, as demonstrated by a 50 and 70% drop in intracellular viability after treatment with the GSH synthesis inhibitor buthionine sulfoximine, and aminonicotinamide (6-ANAM), an inhibitor of G6PDH 6-ANAM, respectively. We concluded that M. leprae could modulate host cell glucose metabolism to increase the cellular reducing power generation, facilitating glutathione regeneration and consequently free-radical control. The impact of this regulation in leprosy neuropathy is discussed.

The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies.

Numerous different pathogens are responsible for infective peripheral neuropathies and this is generally the result of the indirect effects of pathogen infection, namely anti pathogen antibodies cross reacting with epitopes on peripheral nerve, auto reactive T cells attacking myelin, circulating immune complexes and complement fixation. Primary infection of Schwann cells (SC) associated with peripheral nerve inflammation is rare requiring pathogens to cross the Blood Peripheral Nerve Barrier (BPNB) evade anti-pathogen innate immune pathways and invade the SC. Spirochetes Borrelia bourgdorferi and Trepomema pallidum are highly invasive, express surface lipo proteins, but despite this SC are rarely infected. However, Trypanosoma cruzi (Chaga's disease) and Mycobacterium leprae. Leprosy are two important causes of peripheral nerve infection and both demonstrate primary infection of SC. This is due to two novel strategies; T. cruzi express a trans-silalidase that mimics host neurotrophic factors and infects SC via tyrosine kinase receptors. M. leprae demonstrates multi receptor SC tropism and subsequent infection promotes nuclear reprogramming and dedifferentiation of host SC into progenitor stem like cells (pSLC) that are vulnerable to M. leprae infection. These two novel pathogen evasion strategies, involving stem cells and receptor mimicry, provide potential therapeutic targets relevant to the prevention of peripheral nerve inflammation by inhibiting primary SC infection.

STING-Dependent 2'-5' Oligoadenylate Synthetase-Like Production Is Required for Intracellular Mycobacterium leprae Survival.

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen.

Unsolved matters in leprosy: a descriptive review and call for further research.

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and

STING-Dependent 2'-5' oligoadenylate synthetase-like production is required for intracellular Mycobacterium leprae survival

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen.

Subversion of Schwann cell glucose metabolism by Mycobacterium leprae

Mycobacterium leprae, the intracellular etiological agent of leprosy, infects Schwann promoting irreversible physical disabilities and deformities. These cells are responsible for myelination and maintenance of axonal energy metabolism through export of metabolites, such as lactate and pyruvate. In the present work, we observed that infected Schwann cells increase glucose uptake with a concomitant increase in glucose-6-phosphate dehydrogenase (G6PDH) activity, the key enzyme of the oxidative pentose pathway. We also observed a mitochondria shutdown in infected cells and mitochondrial swelling in pure neural leprosy nerves. The classic Warburg effect described in macrophages infected by Mycobacterium avium was not observed in our model, which presented a drastic reduction in lactate generation and release by infected Schwann cells. This effect was followed by a decrease in lactate dehydrogenase isoform M (LDH-M) activity and an increase in cellular protection against hydrogen peroxide insult in a pentose phosphate pathway and GSH-dependent manner. M. leprae infection success was also dependent of the glutathione antioxidant system and its main reducing power source, the pentose pathway, as demonstrated by a 50 and 70% drop in intracellular viability after treatment with the GSH synthesis inhibitor buthionine sulfoximine, and aminonicotinamide (6-ANAM), an inhibitor of G6PDH 6-ANAM, respectively. We concluded that M. leprae could modulate host cell glucose metabolism to increase the cellular reducing power generation, facilitating glutathione regeneration and consequently free-radical control. The impact of this regulation in leprosy neuropathy is discussed.

Downregulation of PHEX in multibacillary leprosy patients: observational cross-sectional study.

BACKGROUND: Peripheral nerve injury and bone lesions, well known leprosy complications, lead to deformities and incapacities. The phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) encodes a homonymous protein (PHEX) implicated in bone metabolism. PHEX/PHEX alterations may result in bone and cartilage lesions. PHEX expression is downregulated by intracellular Mycobacterium leprae (M. leprae) in cultures of human Schwann cells and osteoblasts. M. leprae in vivo effect on PHEX/PHEX is not known. METHODS: Cross-sectional observational study of 36 leprosy patients (22 lepromatous and 14 borderline-tuberculoid) and 20 healthy volunteers (HV). The following tests were performed: PHEX flow cytometric analysis on blood mononuclear cells, cytokine production in culture supernatant, 25-hydroxyvitamin D (OHvitD) serum levels and (99m)Tc-MDP three-phase bone scintigraphy, radiography of upper and lower extremities and blood and urine biochemistry. RESULTS: Significantly lower PHEX expression levels were observed in lepromatous patients than in the other groups (χ(2) = 16.554, p < 0.001 for lymphocytes and χ(2) = 13.933, p = 0.001 for monocytes). Low levels of 25-(OHvitD) were observed in HV (median = 23.0 ng/mL) and BT patients (median = 27.5 ng/mL) and normal serum levels were found in LL patients (median = 38.6 ng/mL). Inflammatory cytokines, such as TNF, a PHEX transcription repressor, were lower after stimulation with M. leprae in peripheral blood mononuclear cells from lepromatous in comparison to BT patients and HV (χ(2) = 10.820, p < 0.001). CONCLUSION: Downregulation of PHEX may constitute an important early component of bone loss and joint damage in leprosy. The present results suggest a direct effect produced by M. leprae on the osteoarticular system that may use this mechanism.

The role of ERBB2 gene polymorphisms in leprosy susceptibility.

Mycobacterium leprae infects skin and peripheral nerves causing deformities and disability. The M. leprae bacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p>0.05) in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. leprae stimulus.

Mechanisms of nerve injury in leprosy.

All patients with leprosy have some degree of nerve involvement. Perineural inflammation is the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of Mycobacterium leprae into nerves. Once inside nerves, M. leprae are ingested by Schwann cells, with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo provides the only animal model of the pathogenesis of M. leprae infection. New tools available for this model enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of nerve injury in leprosy and offers a means of testing proposed interventions.

Mechanisms of nerve injury in leprosy

All patients with leprosy have some degree of nerve involvement. Perineural inflammation is the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of Mycobacterium leprae into nerves. Once inside nerves, M leprae are ingested by Schwann cells, with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo provides the only animal model of the pathogenesis of M leprae infection. New tools available for this model enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of nerve injury in leprosy and offers a means of testing proposed interventions.