title: Mycolates ofMycobacterium tuberculosismodulate the flow of cholesterol for bacillary proliferation in murine macrophages.
abstract: The differentiation of macrophages into lipid-filled foam cells is a hallmark of the lung granuloma that forms in patients with active tuberculosis (TB). Mycolic acids (MAs), the abundant lipid virulence factors in the cell wall ofMycobacterium tuberculosis(Mtb), can induce this foam phenotype possibly as a way to perturb host cell lipid homeostasis to support the infection. It is not exactly clear how MAs allow differentiation of foam cells during Mtb infection. Here we investigated how chemically synthetic MAs, each with a defined stereochemistry similar to natural Mtb-associated mycolates, influence cell foamy phenotype and mycobacterial proliferation in murine host macrophages. Using light and laser-scanning-confocal microscopy, we assessed the influence of MA structure first on the induction of granuloma cell types, second on intracellular cholesterol accumulation, and finally on mycobacterial growth. While methoxy-MAs (mMAs) effected multi-vacuolar giant cell formation, keto-MAs (kMAs) induced abundant intracellular lipid droplets that were packed with esterified cholesterol. Macrophages from mice treated with kMA were permissive to mycobacterial growth, whereas cells from mMA treatment were not. This suggests a separate yet key involvement of oxygenated MAs in manipulating host cell lipid homeostasis to establish the state of TB.
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent Zwijnaarde 9052, Belgium; Department of Biochemistry, University of Pretoria, Pretoria 0002, South Africa.
authors.forename: Ilke
authors.initials: I
authors.lastname: Vermeulen
authors.affiliation: School of Chemistry, Bangor University, Bangor LL57 2UW, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Baird
authors.affiliation: School of Chemistry, Bangor University, Bangor LL57 2UW, United Kingdom.
authors.forename: Juma
authors.initials: J
authors.lastname: Al-Dulayymi
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent Zwijnaarde 9052, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Smet
authors.affiliation: Department of Biochemistry, University of Pretoria, Pretoria 0002, South Africa.
authors.forename: Jan
authors.initials: J
authors.lastname: Verschoor
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent Zwijnaarde 9052, Belgium. Electronic address: Johan.Grooten@irc.ugent.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006099:Granuloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000472:pathogenicity; D009171:Mycolic Acids / Q000008:administration & dosage* / Q000138:chemical synthesis; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
chemical_list: D009171:Mycolic Acids; D002784:Cholesterol
keywords: confocal microscopy; foam cell; infection; lipid droplets; liver X receptor; mycolic acid; tuberculosis