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.

The Continuing Challenges of Leprosy

Laminin (Ln) and collagen are multifunctional glycoproteins that play an important role in cellular morphogenesis, cell signalling, tissue repair and cell migration. These proteins are ubiquitously present in tissues as a part of the basement membrane (BM), constitute a protective layer around blood capillaries and are included in the extracellular matrix (ECM). As a component of BMs, both Lns and collagen(s), thus function as major mechanical containment molecules that protect tissues from pathogens. Invasive pathogens breach the basal lamina and degrade ECM proteins of interstitial spaces and connective tissues using various ECM-degrading proteases or surface-bound plasminogen and matrix metalloproteinases recruited from the host. Most pathogens associated with the respiratory, gastrointestinal, or urogenital tracts, as well as with the central nervous system or the skin, have the capacity to bind and degrade Lns and collagen(s) in order to adhere to and invade host tissues. In this review, we focus on the adaptability of various pathogens to utilize these ECM proteins as enhancers for adhesion to host tissues or as a targets for degradation in order to breach the cellular barriers. The major pathogens discussed are Streptococcus, Staphylococcus, Pseudomonas, Salmonella, Yersinia, Treponema, Mycobacterium, Clostridium, Listeria, Porphyromonas and Haemophilus; Candida, Aspergillus, Pneumocystis, Cryptococcus and Coccidioides; Acanthamoeba, Trypanosoma and Trichomonas; retrovirus and papilloma virus.

Human pathogens utilize host extracellular matrix proteins laminin and collagen for adhesion and invasion of the host

Nerve damage is a clinical hallmark of leprosy and a major source of patient morbidity. We investigated the possibility that human Schwann cells are susceptible to cell death through the activation of Toll-like receptor 2 (TLR2), a pattern recognition receptor of the innate immune system. TLR2 was detected on the surface of human Schwann cell line ST88-14 and on cultured primary human Schwann cells. Activation of the human Schwann cell line and primary human Schwann cell cultures with a TLR2 agonist, a synthetic lipopeptide comprising the N-terminal portion of the putative Mycobacterium leprae 19-kDa lipoprotein, triggered an increase in the number of apoptotic cells. The lipopeptide-induced apoptosis of Schwann cells could be blocked by an anti-TLR2 monoclonal antibody. Schwann cells in skin lesions from leprosy patients were found to express TLR2. It was possible to identify in the lesions Schwann cells that had undergone apoptosis in vivo. The ability of M. leprae ligands to induce the apoptosis of Schwann cells through TLR2 provides a mechanism by which activation of the innate immune response contributes to nerve injury in leprosy.

https://iai.asm.org/content/iai/71/3/1427.full.pdf

Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy

Leprosy, also known as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium leprae, a microorganism that has a predilection for the skin and nerves The disease is clinically characterized by one or more of the three cardinal signs: hypopigmented or erythematous skin patches with definite loss of sensation, thickened peripheral nerves, and acid-fast bacilli detected on skin smears or biopsy material M leprae primarily infects Schwann cells in the peripheral nerves leading to nerve damage and the development of disabilities Despite reduced prevalence of M leprae infection in the endemic countries following implementation of multidrug therapy (MDT) program by WHO to treat leprosy, new case detection rates are still high-indicating active transmission The susceptibility to the mycobacteria and the clinical course of the disease are attributed to the host immune response, which heralds the review of immunopathology of this complex disease

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Leprosy: An Overview of Pathophysiology

The steps in the pathogenesis of nerve injury in leprosy are depicted in Figure 1. Localisation of M. leprae to nerve, Schwann cell infection & responses, as yet unknown mechanisms of injury, axonal atrophy, and finally demyelination. These steps, and the mechanisms responsible for them, occur quickly in the course of this disease (as noted, even the earliest diagnostic lesions have sensory abnormalities), but they are also chronic processes that may contribute to progressive nerve injury over a period of many years unless interrupted by treatment, and even after cure of the infection in some patients. A common feature throughout this pathogenesis is inflammation--within and around the nerve. Inflammation is not only defined by its chemical mediators such as cytokines and chemokines, but by one of the most basic phenomena of inflammation--edema. The extent to which edema might contribute to nerve injury in leprosy has not been reviewed because it has not been studied in nerves affected by leprosy, although clinically, surgeons who perform neurolysis are convinced that they are decompressing nerves sustaining injury due to increased (edematous?) pressure. Inflammation in and around nerves is undoubtedly driven, in part, by the immunological responses in each of the portions of the immunologic spectrum of leprosy, but some inflammatory phenomena may be non-specific inflammation related to infection and foreign material (i.e., mycobacterial components). Few if any fixed associations can be made between the steps outlined in this conceptual framework of events; even the depicted sequence of these events is uncertain. Considerable additional data is needed to determine the connections between these processes and their underlying mechanisms. Additionally, although much emphasis is given to myelinated fibres (and demyelination) in studies of the biology of leprosy neuropathy, the small, sensory fibres in the skin are not myelinated. Additional studies of mechanisms of injury to these nerves is required. The results of all of these studies can be reasonably expected to identify new points for clinical intervention in--and possibly the prevention of--nerve injury in leprosy.

The biology of nerve injury in leprosy.

The ability of Mycobacterium leprae to specifically bind α2-laminins of Schwann cells has been described recently as being an important property of the leprosy bacillus, which could explain the neural tropism of M. leprae. Therefore, the extent of the expression of α2-laminin-binding properties among mycobacteria was investigated. In an ELISA-based assay, all three species of Mycobacterium tested (M. tuberculosis, M. chelonae and M. smegmatis) expressed laminin-binding capacity, suggesting that the ability to bind α2-laminins is conserved within the genus Mycobacterium. This report also demonstrated that not only M. leprae but all the mycobacterial species tested readily interacted with the ST88-14 cells, a human schwannoma cell line, and that the addition of soluble α2-laminins significantly increased their adherence to these cells. These results failed to demonstrate the presence in M. leprae of a unique system based on α2-laminins for adherence to Schwann cells.

V. M. Zhdanov

Papers

Gradual changes of influenza virions during passage of undiluted material.