title: Mycobacterium leprae intracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment.
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 LDL-Cho. 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.
authors.affiliation: Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 21040-900, RJ, Brazil.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Mattos
authors.forename: Viviane C G
authors.initials: VC
authors.lastname: Oliveira
authors.forename: Marcia
authors.initials: M
authors.lastname: Berrêdo-Pinho
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Amaral
authors.forename: Luis Caetano M
authors.initials: LC
authors.lastname: Antunes
authors.forename: Rossana C N
authors.initials: RC
authors.lastname: Melo
authors.forename: Chyntia C D
authors.initials: CC
authors.lastname: Acosta
authors.forename: Danielle F
authors.initials: DF
authors.lastname: Moura
authors.forename: Roberta
authors.initials: R
authors.lastname: Olmo
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Rosa
authors.forename: Patrícia E
authors.initials: PE
authors.lastname: Almeida
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Borchers
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: Georgia C
authors.initials: GC
authors.lastname: Atella
authors.forename: Maria Cristina V
authors.initials: MC
authors.lastname: Pessolani
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D007918:Leprosy / Q000188:drug therapy; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D009166:Mycobacterium leprae / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology*; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics; D051779:Sterol Regulatory Element Binding Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol