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

Abstract

Leprosy is a chronic infectious disease caused byMycobacterium 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 whichM.lepraemodifies the lipid homeostasis in host cells, anin vitro M.lepraeinfection system, using human macrophage precursor THP-1 cells andM.lepraeprepared 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 inM.leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-delta and PPAR-gamma expressions were induced byM.lepraeinfection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-delta or PPAR-gamma antagonist abolished the effect ofM.lepraeto 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 thatM.lepraeinfection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodateM.lepraeparasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy. Author summary Leprosy is a chronic infectious disease caused byMycobacterium leprae(M.leprae). Lipid-enriched intracellular environment is important for the parasitization ofM.leprae. During anti-leprosy treatment, chemotherapy-killed bacilli can remain in host tissues for a long time, making it difficult to determine the treatment efficacy by Zeihl-Nelson's staining-based bacterial index (BI) test. In this study, we found that host peroxisome proliferator-activated receptor (PPAR) signaling is responsible for modification of intracellular lipid homeostasis to accommodateM.lepraeparasitization 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 PPAR target gene expressions were dramatically diminished after the treatment. These results further our understanding ofM.lepraeintracellular parasitization, and suggest that PPAR signaling may be a novel therapeutic target for treatingM.lepraeinfection and monitoring the expressions of certain PPAR target genes in skin lesions may be helpful to evaluate the treatment efficacy and recurrent infection.