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MYCOBACTERIUM LEPRAE INTRACELLULAR SURVIVAL RELIES ON CHOLESTEROL ACCUMULATION IN INFECTED MACROPHAGES: A POTENTIAL TARGET FOR NEW DRUGS FOR LEPROSY TREATMENT
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Abstract
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 LDLCho.
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.
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