Abstract
Mycobacterium leprae (M. leprae) is the etiological agent of leprosy, and the skin lesions of lepromatous leprosy are filled with numerous foamy or xanthomatous histiocytes that are parasitized by M. leprae. Lipids are an important nutrient for the intracellular survival of M. leprae. In this study, we attempted to determine the intracellular lipid composition and underlying mechanisms for changes in host cell lipid metabolism induced by M. leprae infection. Using high-performance thin-layer chromatography (HPTLC), we demonstrated specific induction of triacylglycerol (TAG) production in human macrophage THP-1 cells following M. leprae infection. We then used [14C] stearic acid tracing to show incorporation of this newly synthesized host cell TAG into M. leprae. In parallel with TAG accumulation, expression of host glycerol-3-phosphate acyltransferase 3 (GPAT3), a key enzyme in de novo TAG synthesis, was significantly increased in M. leprae-infected cells. CRISPR/Cas9 genome editing of GPAT3 in THP-1 cells (GPAT3 KO) dramatically reduced accumulation of TAG following M. leprae infection, intracellular mycobacterial load, and bacteria viability. These results together suggest that M. leprae induces host GPAT3 expression to facilitate TAG accumulation within macrophages to maintain a suitable environment that is crucial for intracellular survival of these bacilli.
Highlights
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), which mainly affects the skin and peripheral nerves
The positions of cholesterol ester (ChoE), triacylglycerol (TAG), fatty acid (FA), cholesterol (Cho), diacylglycerol (DAG), monoacylglycerol (MAG) and phospholipid (PL) were determined by their relative to front (RF) values based on the position of standard lipids (S1 Fig)
To clarify whether the observed increase in glycerol-3-phosphate acyltransferase 3 (GPAT3) expression was specific for M. leprae infection, or instead was due to non-specific effects accompanying phagocytosis of particles and/or macrophage activation, we examined the effects of dead M. leprae, latex beads and peptidoglycan on GPAT3 expression
Summary
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), which mainly affects the skin and peripheral nerves. Lepromatous leprosy is a progressive and disseminated disease characterized by widespread skin lesions in which bacilli undergo unrestricted multiplication inside foamy histiocytes In these lesions, M. leprae replicates within enlarged, lipid-filled phagosomes that facilitate its infectious activity [3]. M. leprae suppresses degradation of lipid droplets by suppressing expression of hormone-sensitive lipase (HSL), contributing to a lipid-rich environment in host macrophages [7]. These results suggest that M. leprae infection profoundly modifies host cell lipid metabolism. In Schwann cells, M. leprae stimulates glucose uptake and activates the pentose phosphate pathway that contributes to triacylglycerol (TAG) synthesis [11] Together, these findings demonstrate the importance of host-derived lipids for mycobacteria parasitism. We examined changes in intracellular lipid composition induced by M. leprae infection, as well as underlying molecular mechanisms in macrophages that are involved in these changes
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