title: Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy.
abstract: Intracellular pathogens survive by evading the host immune system and accessing host metabolic pathways to obtain nutrients for their growth. Mycobacterium leprae, the causative agent of leprosy, is thought to be the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Although fatty acids and phospholipids accumulate in the lesions of individuals with the lepromatous (also known as disseminated) form of human leprosy (L-lep), the origin and significance of these lipids remains unclear. Here we show that in human L-lep lesions, there was preferential expression of host lipid metabolism genes, including a group of phospholipases, and that these genes were virtually absent from the mycobacterial genome. Host-derived oxidized phospholipids were detected in macrophages within L-lep lesions, and 1 specific oxidized phospholipid, 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphorylcholine (PEIPC), accumulated in macrophages infected with live mycobacteria. Mycobacterial infection and host-derived oxidized phospholipids both inhibited innate immune responses, and this inhibition was reversed by the addition of normal HDL, a scavenger of oxidized phospholipids, but not by HDL from patients with L-lep. The accumulation of host-derived oxidized phospholipids in L-lep lesions is strikingly similar to observations in atherosclerosis, which suggests that the link between host lipid metabolism and innate immunity contributes to the pathogenesis of both microbial infection and metabolic disease.
authors.affiliation: Division of Cardiology, Molecular Biology Institute, Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Howard Hughes Medical Institute, Los Angeles, California 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cruz
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Watson
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Miller
authors.forename: Dennis
authors.initials: D
authors.lastname: Montoya
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Ochoa
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gutierrez
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
authors.forename: Judith
authors.initials: J
authors.lastname: Berliner
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D028421:Isoprostanes / Q000096:biosynthesis; D007918:Leprosy / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D009000:Monocytes / Q000502:physiology; D009166:Mycobacterium leprae / Q000235:genetics; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010743:Phospholipids / Q000378:metabolism* / Q000502:physiology
chemical_list: C500237:1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphocholine; D028421:Isoprostanes; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D010743:Phospholipids