Deciphering the contribution of lipid droplets in leprosy: multifunctional organelles with roles in Mycobacterium leprae pathogenesis

Mattos, Katherine Antunes de; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal; Bozza, Patrı́cia T.

doi:10.1590/s0074-02762012000900023

Cited by 46 publications

(41 citation statements)

References 66 publications

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“…[13] Eicosanoid metabolism was also observed in M. leprae-induced lipid droplets, where cycloxygenase-2 activity and PGE 2 production were demonstrated. [47] PLs putatively containing either omega-3 (m/z 756.7, PC 34:3) or omega-6 (m/z 758.7, PC 34:2; m/z 766.4, PE 38:4; and m/z 885.5, PI 38:4) FA moieties at the sn-2 position were detected in our study. Noteworthy in the case of PCs was a tendency for a higher mean gray value for omega-3 containing species before treatment, whereas the contrary for omega-6 was observed.…”

Section: Discussionsupporting

confidence: 49%

“…Furthermore, the presence of intense omega‐3 and omega‐6 metabolism in serum and skin biopsies of LL patients was observed . Eicosanoid metabolism was also observed in M. leprae ‐induced lipid droplets, where cycloxygenase‐2 activity and PGE 2 production were demonstrated . PLs putatively containing either omega‐3 ( m/z 756.7, PC 34:3) or omega‐6 ( m/z 758.7, PC 34:2; m/z 766.4, PE 38:4; and m/z 885.5, PI 38:4) FA moieties at the sn‐2 position were detected in our study.…”

Section: Discussionmentioning

confidence: 99%

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MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT)

et al. 2015

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Leprosy still represents a health problem in several countries. Affecting skin and peripheral nerves, it may lead to permanent disabilities. Disturbances on skin lipid metabolism in leprosy were already observed; however, the localization and distribution of lipids could not be accessed. The role of lipids on infectious disease has been fully addressed only recently, as they directly influence immune response. Matrix-assisted laser desorption/ionization imaging mass spectrometry provides a powerful tool to localize and identify lipids in tissues. The aim of this work was to study and compare the changes in lipid distribution of skin biopsies taken from leprosy patients before and after multidrug therapy (MDT). Different species of phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin and phosphatidylcholine were detected. Differences in skin lipid signal intensities, as well as in their localization, were observed before and after MDT in every patient. In general, lipid distribution in the skin after MDT had a pattern similar to control skin samples, where most of the lipids were located in the upper part of the dermis and epidermis. This study opens paths to a better understanding of lipid functions in leprosy pathogenesis and immune response.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT)

et al. 2015

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“…A vast body of evidence indicates that lipid-laden, infected cells perform a key pathophysiological role in tuberculosis and leprosy (Peyron et al, 2008;Bozza et al, 2009;Elamin et al, 2012;de Mattos et al, 2012;Saka and Valdivia, 2012;Singh et al, 2012). In view of the importance of this foamy phenotype in mycobacterial disease, an investigation was undertaken into the cellular mechanisms triggered by ML to display this shift in lipid metabolism in infected macrophages.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium lepraeintracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment

et al. 2014

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We recently showed that Mycobacterium leprae (ML) is able to induce lipid droplet formation in infected macrophages. We herein confirm that cholesterol (Cho) is one of the host lipid molecules that accumulate in ML-infected macrophages and investigate the effects of ML on cellular Cho metabolism responsible for its accumulation. The expression levels of LDL receptors (LDL-R, CD36, SRA-1, SR-B1, and LRP-1) and enzymes involved in Cho biosynthesis were investigated by qRT-PCR and/or Western blot and shown to be higher in lepromatous leprosy (LL) tissues when compared to borderline tuberculoid (BT) lesions. Moreover, higher levels of the active form of the sterol regulatory element-binding protein (SREBP) transcriptional factors, key regulators of the biosynthesis and uptake of cellular Cho, were found in LL skin biopsies. Functional in vitro assays confirmed the higher capacity of ML-infected macrophages to synthesize Cho and sequester exogenous LDL-Cho. Notably, Cho colocalized to ML-containing phagosomes, and Cho metabolism impairment, through either de novo synthesis inhibition by statins or depletion of exogenous Cho, decreased intracellular bacterial survival. These findings highlight the importance of metabolic integration between the host and bacteria to leprosy pathophysiology, opening new avenues for novel therapeutic strategies to leprosy.

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“…bovis [4] and M . leprae [5], and was not observed upon infection with non-pathogenic species, such as M . smegmatis [3].…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium marinum Degrades Both Triacylglycerols and Phospholipids from Its Dictyostelium Host to Synthesise Its Own Triacylglycerols and Generate Lipid Inclusions

Barisch

Soldati

2017

PLoS Pathog

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During a tuberculosis infection and inside lipid-laden foamy macrophages, fatty acids (FAs) and sterols are the major energy and carbon source for Mycobacterium tuberculosis. Mycobacteria can be found both inside a vacuole and the cytosol, but how this impacts their access to lipids is not well appreciated. Lipid droplets (LDs) store FAs in form of triacylglycerols (TAGs) and are energy reservoirs of prokaryotes and eukaryotes. Using the Dictyostelium discoideum/Mycobacterium marinum infection model we showed that M. marinum accesses host LDs to build up its own intracytosolic lipid inclusions (ILIs). Here, we show that host LDs aggregate at regions of the bacteria that become exposed to the cytosol, and appear to coalesce on their hydrophobic surface leading to a transfer of diacylglycerol O-acyltransferase 2 (Dgat2)-GFP onto the bacteria. Dictyostelium knockout mutants for both Dgat enzymes are unable to generate LDs. Instead, the excess of exogenous FAs is esterified predominantly into phospholipids, inducing uncontrolled proliferation of the endoplasmic reticulum (ER). Strikingly, in absence of host LDs, M. marinum alternatively exploits these phospholipids, resulting in rapid reversal of ER-proliferation. In addition, the bacteria are unable to restrict their acquisition of lipids from the dgat1&2 double knockout leading to vast accumulation of ILIs. Recent data indicate that the presence of ILIs is one of the characteristics of dormant mycobacteria. During Dictyostelium infection, ILI formation in M. marinum is not accompanied by a significant change in intracellular growth and a reduction in metabolic activity, thus providing evidence that storage of neutral lipids does not necessarily induce dormancy.

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Deciphering the contribution of lipid droplets in leprosy: multifunctional organelles with roles in Mycobacterium leprae pathogenesis

Abstract: Leprosy is an infectious disease caused by

Cited by 46 publications

References 66 publications

MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT)

MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT)

Mycobacterium lepraeintracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment

Mycobacterium marinum Degrades Both Triacylglycerols and Phospholipids from Its Dictyostelium Host to Synthesise Its Own Triacylglycerols and Generate Lipid Inclusions

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