Modulation of the Response to Mycobacterium leprae and Pathogenesis of Leprosy

Abstract

The initial infection by the obligate intracellular bacillus Mycobacterium leprae evolves to leprosy in a small subset of the infected individuals. Transmission is believed to occur mainly by exposure to bacilli present in aerosols expelled by infected individuals with high bacillary load. Mycobacterium leprae-specific DNA has been detected in the blood of asymptomatic household contacts of leprosy patients years before active disease onset, suggesting that, following infection, the bacterium reaches the lymphatic drainage and the blood of at least some individuals. The lower temperature and availability of protected microenvironments may provide the initial conditions for the survival of the bacillus in the airways and skin. A subset of skin-resident macrophages and the Schwann cells of peripheral nerves, two M. leprae permissive cells, may protect M. leprae from effector cells in the initial phase of the infection. The interaction of M. leprae with these cells induces metabolic changes, including the formation of lipid droplets, that are associated with macrophage M2 phenotype and the production of mediators that facilitate the differentiation of specific T cells for M. leprae-expressed antigens to a memory regulatory phenotype. Here, we discuss the possible initials steps of M. leprae infection that may lead to active disease onset, mainly focusing on events prior to the manifestation of the established clinical forms of leprosy. We hypothesize that the progressive differentiation of T cells to the Tregs phenotype inhibits effector function against the bacillus, allowing an increase in the bacillary load and evolution of the infection to active disease. Epigenetic and metabolic mechanisms described in other chronic inflammatory diseases are evaluated for potential application to the understanding of leprosy pathogenesis. A potential role for post-exposure prophylaxis of leprosy in reducing M. leprae-induced anti-inflammatory mediators and, in consequence, Treg/T effector ratios is proposed.

Keywords: FOXP-3; interferon-γ; leprosy pathogenesis; lipid droplets; memory T cells; polyunsaturated fatty acid metabolites; regulatory T cells.

Figure 1

Evolution of asymptomatic infection to active disease. Following exposure to Mycobacterium leprae, only a few people develop Leprosy. The progression to active disease is accompanied by immunologic and metabolic changes, such as downregulation of TH1 cytokines, production of antibodies (anti-PGL-I and LID-1), and lipid mediators. DNA of M. leprae in blood samples also indicates individuals with an increased risk of disease onset. Leprosy patients may present alterations in upper airways, skin, and peripheral nerves, depending on the host immune cells involved in the response against M. leprae. DNA-ML, DNA of M. leprae; PGL-I, Phenolic Glycolipid I; LID-1, leprosy IDRI diagnostic-1; RvD1, Resolvin D1; PGE₂, Prostaglandin E₂; PGD₂, Prostaglandin D₂; LXA₄, Lipoxin A₄; HLP, Histone-like protein; HBHA, hemagglutinin binding heparin; AgTregs, antigen-specific regulatory T cells; PUFAs, Polyunsaturated fatty acids; Teff, effector T cells; Laminin 2 α-DG, Laminin 2 α Dystroglycan; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9. Created with smart.servier.com.

Figure 2

Epigenetic modifications as potential biomarkers. Epigenetic markers, including DNA methylation, histone modifications, and non-coding RNAs, have a great potential as biomarkers for chronic inflammatory diseases. In pemphigus vulgaris (PV), the miR338-3p expression is increased in patients and is positively correlated with disease severity. Changes in the miRNAs profile in tuberculosis (TB), as well as changes in DNA methylation of immune cells genes, may be useful as early diagnostic tools for the disease. In psoriasis (PsO), methylation profile of several genes has been associated with the severity of the disease and response to therapies. In leprosy, hsa-miR-155 and piR-hsa-27283 are upregulated in skin lesions, whereas hsa-miR-1291 is upregulated in the blood of patients. These non-coding RNAs can be tested as biomarkers for the disease. The methylation profile of FOXP3 has been used as a biomarker of prognosis in other diseases and may be used in leprosy as well. However, new studies are required. The levels of FOXP3-HDAC7/9, and FOXP3-HAT complexes in leprosy are associated with functional competence, whereas hypomethylation patterns in FOXP3 promoter support FOXP3 expression. Epigenetic alterations may be useful biomarkers with diagnostic, prognostic, predictive, or therapeutic potential for chronic inflammatory diseases. HDAC, histone deacetylases; HAT, Histone acetyltransferases; PPP, pentose phosphate pathway. Created with smart.servier.com.

Figure 3

Regulatory and effector T cells balance in leprosy pathogenesis. The increased exposure to Mycobacterium leprae in household contacts of leprosy patients, as well as the increased bacillary load in patients, may alter the balance between antigen-specific regulatory T cells (Treg) and effector T cells (Teff). If the ratio within antigen-specific T cells is toward Teff cells, there will be protective cell-mediated immune responses against M. leprae. However, if the number of Treg cells increases and reaches an equilibrium or exceeds the frequency of Teff cells, effector function against M. leprae will be compromised, and the infection will more likely progress to active disease. Teff, effector T cells; Treg, Regulatory T cells; HCPB, household contacts of paucibacillary patients; HCMB, household contacts of multibacillary patients; PB, paucibacillary patients; MB, multibacillary patients. Created with smart.servier.com.