by (E) Functional assessment of HDL from leprosy patients. and disseminates, intracellular bacteria are abundant, and cell-mediated immunity to the pathogen is usually weak or absent. In terms of the innate immune response, a key correlate is the DC, abundant in T-lep lesions compared with L-lep lesions and expressing the antigen presentation molecules CD1a, CD1b, and CD1c, which present mycobacterial lipids to T cells (6, 7). Furthermore, there is greater expression in T-lep lesions of TLR2/1 (8), pattern recognition receptors that mediate the response to mycobacterial lipoproteins and lead to production of IL-12 and IL-10, key cytokines that instruct the adaptive T cell response. The link between the innate and adaptive response is usually further apparent in the increased frequency of 0.05; fold change 1.5) were organized according to biologic processes and pathways. Although interindividual variation was noted, perhaps in part as a result MTC1 of heterogeneity RPH-2823 of disease lesions and genetic background, a striking pattern emerged. In L-lep lesions, host lipid metabolism genes accounted for 11% of the differentially upregulated genes, making it the third largest category of genes more highly expressed in L-lep than in T-lep lesions (Physique ?(Figure1A).1A). The categories that contained greater percentages of upregulated genes were signaling/gene regulation members and immune response genes, at 25% and 13%, respectively. In comparing the absolute number of genes upregulated in L-lep versus T-lep lesions, the number of host lipid metabolism genes was approximately 4-fold greater in L-lep lesions than in T-lep lesions (Physique ?(Figure1B).1B). This was not the case for all those metabolism genes; in fact, the number of protein metabolism genes upregulated in L-lep lesions was approximately half that of T-lep lesions. Open in a separate window Physique 1 Differential expression of host lipid metabolism genes in polar forms of leprosy.(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 (= 6 lesions) and T-lep lesions (= 5 lesions) were subcategorized according to function and listed by ascending value. All genes had at least 1.5-fold relative expression and 0.05. The host lipid metabolism genes upregulated in L-lep lesions were further divided into RPH-2823 functional subcategories according to metabolic function (Physique ?(Physique1C).1C). In L-lep lesions, the most frequent groups of upregulated host lipid metabolism genes were those involved in lipoprotein metabolism and fatty acid metabolism, including lipases involved in lipid catabolism. These categories accounted for more than one-third of the upregulated lipid metabolism genes. Several genes associated with the recognition, metabolism, and degradation of RPH-2823 oxidized phospholipids were among the most highly induced; these included scavenger receptors that promote uptake of oxidatively modified lipoproteins (e.g., MSR, MARCO, and CD36L receptor), enzymes important for degrading oxidized fatty acid moieties on phospholipid oxidation products (e.g., epoxide hydrolase and aldehyde dehydrogenase), and phospholipases that hydrolyze phospholipids (e.g., platelet activating factor acetyl hydrolase, neuropathy target esterase, and 4 phospholipase C genes). Together, 9 different host lipases with the capacity to metabolize phospholipids were upregulated in L-lep lesions. There were 13 host lipid metabolism genes upregulated in T-lep lesions (Physique ?(Physique1C),1C), with no more than 2 belonging to a particular subclass. Comparative analysis of the mycobacterial genome and host transcriptome. The induction of host phospholipases in L-lep lesions led us to hypothesize that host metabolic pathways were being recruited to complement deficiencies in the genome. The genome has a paucity of lipase genes, with only 1 1 potential gene, genome (15). We.
