Mycobacterium lepraeintracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment

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We recently showed that Mycobacterium leprae (ML) is able to induce lipid droplet formation in infected macrophages. We herein confirm that cholesterol (Cho) is one of the host lipid molecules that accumulate in ML-infected macrophages and investigate the effects of ML on cellular Cho metabolism responsible for its accumulation. The expression levels of LDL receptors (LDL-R, CD36, SRA-1, SR-B1, and LRP-1) and enzymes involved in Cho biosynthesis were investigated by qRT-PCR and/or Western blot and shown to be higher in lepromatous leprosy (LL) tissues when compared to borderline tuberculoid (BT) lesions. Moreover, higher levels of the active form of the sterol regulatory element-binding protein (SREBP) transcriptional factors, key regulators of the biosynthesis and uptake of cellular Cho, were found in LL skin biopsies. Functional in vitro assays confirmed the higher capacity of ML-infected macrophages to synthesize Cho and sequester exogenous LDL-Cho. Notably, Cho colocalized to ML-containing phagosomes, and Cho metabolism impairment, through either de novo synthesis inhibition by statins or depletion of exogenous Cho, decreased intracellular bacterial survival. These findings highlight the importance of metabolic integration between the host and bacteria to leprosy pathophysiology, opening new avenues for novel therapeutic strategies to leprosy.

The accumulation of lipids in Mycobacterium leprae-infected cells is a hallmark of lepromatous leprosy. We herein found that M. leprae increases cholesterol de novo synthesis and the uptake of exogenous cholesterol in infected macrophages by upregulating the expression of host genes involved in these pathways. Notably, cholesterol metabolism impairment significantly decreased intracellular bacterial survival, suggesting that the use of statins, among the most frequently prescribed drugs worldwide, could lead to improvements in the outcomes of leprosy therapy.

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