Oxidized low-density lipoprotein (oxLDL) supports Mycobacterium tuberculosis survival in macrophages by inducing lysosomal dysfunction

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.

Foam Cells Control Mycobacterium tuberculosis Infection

“…Together with the evidence associating non-replicating persistence with phenotypic drug tolerance (Gold and Nathan, 2017), this link has underpinned the notion that ILI-containing bacilli, such as those detected in the sputum of TB patients, are "fat and lazy" (Garton et al, 2008) and phenotypically drug tolerant (Turapov et al, 2016). However, in contrast to these studies, Mtb showed no significant growth impairment in necrosis-associated foamy macrophages (NFAMs) (Jaisinghani et al, 2018) and showed even better growth in human macrophages which became foam cells by incubation with oxidized low-density lipoprotein than in resting macrophages (Vrieling et al, 2019), further highlighting differences between the various models.…”

IGFBP6 Is Downregulated in Unstable Carotid Atherosclerotic Plaques According to an Integrated Bioinformatics Analysis and Experimental Verification

“…In this work, the upregulated gene in unstable carotid plaque was enriched in the tuberculous pathways; this result may imply that tuberculosis infection is correlated with plaque instability. The treatment of oxidized low-density lipoprotein inhibits macrophage lysosomes from combining with Mycobacterium tuberculosis , thereby supporting the survival of the microorganism 33 ) . Atherosclerosis may in turn drive the development of tuberculosis.…”

Peritoneal macrophages have an impaired immune response in obesity which can be reversed by subsequent weight loss

“…These metabolic changes may play a role in the mechanism of the deactivated phenotype since metabolism and macrophage function are highly dependent 36. For instance, it has been shown that T2D promotes an impaired control of M. tuberculosis in human foamy macrophages by inducing lysosomal dysfunction 37. Additionally, previous work has shown that PMs from Ldlr −/− mice fed a Western diet show a deactivated phenotype 23 38.…”