The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in Mycobacterium leprae-induced foam cell formation in host macrophages.

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.

[Mycobacterium leprae: behavior in the adipocyte undergoing differentiation]. / Mycobacterium leprae: comportement dans l'adipocyte en voie de différenciation.

We have investigated the behaviour of M. leprae in murine preadipocyte cells (clone Ob17) undergoing the adipose cell conversion process in vitro. Actively differentiating Ob17 cells were infected with M. leprae. The morphological index (MI) of the acid-fast bacteria (AFB) present at day 12 and day 25 after infection was compared to the MI of the AFB inoculated. An increase of the MI was consistently observed. This increase is suppressed by rifampicin. Due to important cell loss, an increase of the number of the AFB per culture could not be obtained in monolayer tissue cultures. In order to prevent cell loss, we used a three-dimensional culture system. This cell culture system is an in vitro reconstitution of the human dermis, a main target organ for the leprosy bacillus. Adipocytes infected with M. leprae are incorporated in a condensed collagen lattice together with skin fibroblasts. Under such conditions, both an increase of the MI and an increase of the number of the AFB are obtained. This suggests that cellular functions related to the adipose cell differentiation process might complement the defective bacterial genome, leading to transient multiplication in vitro.