Abstract
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.
Highlights
Leprosy is an ancient chronic infectious disease caused by M. leprae, an indolent-growing obligate intracellular bacterial pathogen
We found that host peroxisome proliferatoractivated receptor (PPAR) signaling is responsible for modification of intracellular lipid homeostasis to accommodate M. leprae parasitization in host macrophages
In skin smear samples of patients, M. leprae-derived gene expressions were detected both before and after anti-leprosy treatment, whereas human peroxisome proliferator-activated receptor (PPAR) target gene expressions were dramatically diminished after the treatment
Summary
Leprosy is an ancient chronic infectious disease caused by M. leprae, an indolent-growing obligate intracellular bacterial pathogen. Despite the success of multidrug therapy (MDT) that has reduced the leprosy burden over years, this disease remains an important cause of morbidity in many developing countries, with over 200,000 new cases reported worldwide annually [1]. During the course of MDT, an acute aggravating episode known as lepra reaction, which is putatively triggered by an intense immune response to the chemotherapy-uncovered bacilli antigens, can occur and may cause severe and irreversible nerve damage [2]. MDT-killed bacilli can remain in host tissues for a long time, which can be detected in Zeihl-Nelson’s staining-based bacterial index (BI) test. It is still important to explore new approaches to control infection and to evaluate host response to anti-leprosy treatment
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