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

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.

Whole Genome Sequencing Highlights the Pathogenic Profile in Nocardia Keratitis

“…For encoding a cholesterol transporter, 50,51 mce4 contributes to the entrance of Nocardia into a tryptophan aspartate-containing coat protein (TACO) -coated phagosomes to prevent the degradation of lysosomes, 52 meanwhile promoting the localization and invasion of Nocardia to host cells through cholesterol-rich domains of the plasma membrane. 53,54 Furthermore, mce4C and mce4F genes allow Nocardia to grow under hypoxic conditions, by taking in cholesterol as a carbon source, therefore, providing energy for Nocardia survival inside the cornea and deeper invasion. 48 All strains in group C contained the mce4F gene, thus obtaining similar basic pathogenic properties to group B. Mce4F, an essential component of the mce4 operon, is found in the genomes of mycobacteria and Nocardia.…”

Essential Roles of PPARs in Lipid Metabolism during Mycobacterial Infection

“…Conversely, high-performance thin-layer chromatography (HPTLC) analysis demonstrates that TAG is the main component of the lipid in M. leprae -infected human monocytic THP-1 cells [ 62 ]. It has been reported in Schwann cells that M. leprae infection enhances glucose uptake and stimulates the pentose phosphate pathway, which is required for TAG synthesis [ 63 ].…”

“…The accumulated TAGs are maintained by the enhanced expression of adipose differentiation-related protein (ADRP) and perilipin and by the reduced expression of hormone-sensitive lipase (HSL), which contributes to lipid degradation [ 64 , 65 ]. Glycerol-3-phosphate acyltransferase 3 (GPAT3) is an important rate-limiting enzyme for TAG synthesis [ 66 ]; accordingly, the internalization and viability of bacilli are lower in GPAT3 knockout cells [ 62 ]. Furthermore, clofazimine, a therapeutic agent for leprosy, reduces the accumulation of lipid in M. leprae -infected THP-1 cells and promotes the production of interferon (IFN)-β and IFN-γ [ 67 ].…”

“…Activation of the PPAR-γ signaling pathway is responsible for the upregulation of Gpat3 expression during adipocyte differentiation [ 73 , 74 , 75 ]. We also found that GPAT3 expression is induced in THP-1 cells infected with M. leprae , suggesting that the mechanism of intracellular TAG accumulation is triggered by PPAR-γ activation [ 62 ].…”

Microbes, Clinical trials, Drug Discovery, and Vaccine Development: The Current Perspectives

“…While culturing the microbes that cause diseases, it is observed that some microbes require different media/bases/supplements for their culture. Some do not grow in artificial media and may only be maintained in laboratory animals (Leptospira, Mycobacterium leprae, Mycoplasma pneumoniae) [25][26][27] . The clinical research knowledge may be used to develop new media to grow such microbes.…”