Browsing by Author "Vrieling, Frank"

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    Oxidized low-density lipoprotein (oxLDL) supports Mycobacterium tuberculosis survival in macrophages by inducing lysosomal dysfunction
    (Public Library of Science, 2019) Vrieling, Frank; Wilson, Louis; Rensen, Patrick C. N.; Walzl, Gerhard; Ottenhoff, Tom H. M.; Joosten, Simone A.
    ENGLISH ABSTRACT: Type 2 diabetes mellitus (DM) is a major risk factor for developing tuberculosis (TB). TB-DM comorbidity is expected to pose a serious future health problem due to the alarming rise in global DM incidence. At present, the causal underlying mechanisms linking DM and TB remain unclear. DM is associated with elevated levels of oxidized low-density lipoprotein (oxLDL), a pathologically modified lipoprotein which plays a key role during atherosclerosis development through the formation of lipid-loaded foamy macrophages, an event which also occurs during progression of the TB granuloma. We therefore hypothesized that oxLDL could be a common factor connecting DM to TB. To study this, we measured oxLDL levels in plasma samples of healthy controls, TB, DM and TB-DM patients, and subsequently investigated the effect of oxLDL treatment on human macrophage infection with Mycobacterium tuberculosis (Mtb). Plasma oxLDL levels were significantly elevated in DM patients and associated with high triglyceride levels in TB-DM. Strikingly, incubation with oxLDL strongly increased macrophage Mtb load compared to native or acetylated LDL (acLDL). Mechanistically, oxLDL -but not acLDL- treatment induced macrophage lysosomal cholesterol accumulation and increased protein levels of lysosomal and autophagy markers, while reducing Mtb colocalization with lysosomes. Importantly, combined treatment of acLDL and intracellular cholesterol transport inhibitor (U18666A) mimicked the oxLDL-induced lysosomal phenotype and impaired macrophage Mtb control, illustrating that the localization of lipid accumulation is critical. Collectively, these results demonstrate that oxLDL could be an important DM-associated TB-risk factor by causing lysosomal dysfunction and impaired control of Mtb infection in human macrophages.
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    Patients with concurrent tuberculosis and diabetes have a pro-atherogenic plasma lipid profile
    (Elsevier, 2018) Vrieling, Frank; Ronacher, Katharina; Kleynhans, Leanie; Van Den Akker, Erik; Walzl, Gerhard; Ottenhoff, Tom H. M.; Joosten, Simone A.
    Background: Type 2 diabetes mellitus (DM) is a major risk factor for development of tuberculosis (TB), however the underlyingmolecular foundations are unclear. Since lipids play a central role in the development of both DM and TB, lipid metabolism may be important for TB-DM pathophysiology. Methods: A 1H NMR spectroscopy-based platform was used to determine 225 lipid and other metabolic intermediates in plasma samples of healthy controls (n=50) and patients with TB (n=50), DM(n=50) or TB-DM (n = 27). Results: TB patients presented with wasting disease, represented by decreased amino acid levels including histidine and alanine. Conversely, DM patients were dyslipidemic as evidenced by high levels of very lowdensity lipoprotein triglycerides and low high-density lipoprotein cholesterol. TB-DM patients displayed metabolic characteristics of both wasting and dyslipidemia combined with disease interaction-specific increases in phospholipid metabolites (e.g. sphingomyelins) and atherogenic remnant-like lipoprotein particles. Biomarker analysis identified the ratios of phenylalanine/histidine and esterified cholesterol/ sphingomyelin as markers for TB classification regardless of DM-status. Conclusions: TB-DM patients possess a distinctive plasma lipid profile with pro-atherogenic properties. These findings support further research on the benefits of improved blood lipid control in the treatment of TB-DM.