Mycobacterium leprae promotes triacylglycerol de novo synthesis through induction of GPAT3 expression in human premonocytic THP-1 cells

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 [ 14 C] 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.