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Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy
Daniel Cruz, … , Judith Berliner, Robert L. Modlin
Daniel Cruz, … , Judith Berliner, Robert L. Modlin
Published July 17, 2008
Citation Information: J Clin Invest. 2008;118(8):2917-2928. https://doi.org/10.1172/JCI34189.
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Research Article

Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy

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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

Daniel Cruz, Andrew D. Watson, Christopher S. Miller, Dennis Montoya, Maria-Teresa Ochoa, Peter A. Sieling, Miguel A. Gutierrez, Mohamad Navab, Srinivasa T. Reddy, Joseph L. Witztum, Alan M. Fogelman, Thomas H. Rea, David Eisenberg, Judith Berliner, Robert L. Modlin

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Figure 1

Differential expression of host lipid metabolism genes in polar forms of leprosy.

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Differential expression of host lipid metabolism genes in polar forms of...
(A) Genes preferentially expressed in L-lep lesions were categorized according to metabolic function. (B) L-lep lesions preferentially expressed a greater number of lipid metabolism genes, but fewer genes involved in protein metabolism, compared with T-lep lesions. (C) Lipid metabolism genes preferentially expressed in L-lep lesions (n = 6 lesions) and T-lep lesions (n = 5 lesions) were subcategorized according to function and listed by ascending P value. All genes had at least 1.5-fold relative expression and P < 0.05.

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