The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production
ABSTRACTMycobacterium lepraeinduces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance inM. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity ofM. lepraeto acquire and metabolize cholesterol.In silicoanalyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen inMycobacterium tuberculosispreserved byM. leprae. Incubation of bacteria with radiolabeled cholesterol confirmed thein silicopredictions. Radiorespirometry and lipid analyses performed after incubatingM. lepraewith [4-14C]cholesterol or [26-14C]cholesterol showed the inability of this pathogen to metabolize the sterol rings or the side chain of cholesterol as a source of energy and carbon. However, the bacteria avidly incorporated cholesterol and, as expected, converted it to cholestenone bothin vitroandin vivo. Our data indicate thatM. lepraehas lost the capacity to degrade and utilize cholesterol as a nutritional source but retains the enzyme responsible for its oxidation to cholestenone. Thus, the essential role of cholesterol metabolism in the intracellular survival ofM. lepraeis uncoupled from central carbon metabolism and energy production. Further elucidation of cholesterol metabolism in the host cell duringM. lepraeinfection will establish the mechanism by which this lipid supportsM. lepraeintracellular survival and will open new avenues for novel leprosy therapies.IMPORTANCEOur study focused on the obligate intracellular pathogenMycobacterium lepraeand its capacity to metabolize cholesterol. The data make an important contribution for those interested in understanding the mechanisms of mycobacterial pathogenesis, since they indicate that the essential role of cholesterol forM. lepraeintracellular survival does not rely on its utilization as a nutritional source. Our findings reinforce the complexity of cholesterol's role in sustainingM. lepraeinfection. Further elucidation of cholesterol metabolism in the host cell duringM. lepraeinfection will establish the mechanism by which this lipid supportsM. lepraeintracellular survival and will open new avenues for novel leprosy therapies.