Aminopeptidase <scp>N</scp> facilitates entry and intracellular survival of <i><scp>M</scp>ycobacterium tuberculosis</i> in monocytes

Ho, Hsin‐Tsung; Tsai, I-Fang; Wu, Chien‐Liang; Lu, Yen‐Ta

doi:10.1111/resp.12191

Cited by 7 publications

(9 citation statements)

References 33 publications

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“…Therefore, reduction of plasma lipids may not be fully effective at controlling latent TB. In fact, our previous study showed that another lipid-lowering agent, ezetimibe, known to inhibit cholesterol uptake into cells, was associated with a lower risk of latent TB in patients with diabetes [29][30][31]. Our current study shows that fenofibrate not only sustains the availability of intracellular lipids but also enhances dormant genes known to involved in lipid metabolism.…”

Section: Discussionmentioning

confidence: 51%

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Liu

Tsai

et al. 2020

JCM

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Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate. people, it still presents the highest incidence and mortality rate [2]. This disease is transmitted via inhalation of aerosolized bacilli, which then replicate within alveolar macrophages in lung tissue. In the host, immune cells can be recruited to the affected sites, and encase the invading mycobacteria, forming a structure known as the granuloma [3,4]. A granuloma is composed of infected alveolar macrophages, monocytes, multinucleated giant cells, epithelioid cells, and most notably, foamy macrophages [4,5]. The foamy aspect of these cells results from the accumulation of neutral lipids, typically triacylglycerides and esterified and non-esterified sterols. These foamy macrophages are nutrient-rich reservoirs for Mtb persistence [6,7].Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10]. By the activation of peroxisome proliferator activated receptor α (PPARα), mainly expressed in the liver, heart, monocytes, and macrophages, fenofibrate increases lipolysis and elimination of lipids from plasma [11][12][13]. It is commonly prescribed for the treatment of hypertriglyceridemia or mixed hyperlipidemia [13][14][15]. This study aimed to investigate epidemiological data to obtain outcomes of TB...

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Section: Discussionmentioning

confidence: 51%

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Liu

Tsai

et al. 2020

JCM

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“…Although our STRING analysis didn’t reveal the direct association between CD13 and phagosome acidification-related proteins, CD13 has been reported to not only be a receptor on mycobacteria, but also a mediator that participates in phagosome acidification during M. tuberculosis infection [ 25 ]. As a result, further analysis is needed to clarify CD13’s interactions with phagosome acidication-related proteins.…”

Section: Discussionmentioning

confidence: 95%

“…However, the physiological relevance of this high expression is not fully understood yet. We have previously reported that CD13 serves as a receptor on monocyte/macrophages that binds to M. tuberculosis [ 25 ], as well as a possible receptor that mediates of lipid uptake (unpublished observations, [ 30 ]). Via proteomics data and STRING analysis, we demonstrated that the highly-expressed CD13 is also associated with proteins involved in the antigen presenting process, especially with CD1 proteins.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the immune response of human dendritic cells to Mycobacterium tuberculosis by quantitative proteomics

et al. 2016

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BackgroundThe cellular immune response for Mycobacterium tuberculosis (M. tuberculosis) infection remained incompletely understood. To uncover membrane proteins involved in this infection mechanism, an integrated approach consisting of an organic solvent-assisted membrane protein digestion, stable-isotope dimethyl labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to comparatively profile the membrane protein expression of human dendritic cells upon heat-killed M. tuberculosis (HKTB) treatment.ResultsOrganic solvent-assisted trypsin digestion coupled with stable-isotope labeling and LC-MS/MS analysis was applied to quantitatively analyze the membrane protein expression of THP-1 derived dendritic cells. We evaluated proteins that were upregulated in response to HKTB treatment, and applied STRING website database to analyze the correlations between these proteins. Of the investigated proteins, aminopeptidase N (CD13) was found to be largely expressed after HKTB treatment.By using confocal microscopy and flow cytometry, we found that membranous CD13 expression was upregulated and was capable of binding to live mycobacteria. Treatment dendritic cell with anti-CD13 antibody during M. tuberculosis infection enhanced the ability of T cell activation.ConclusionsVia proteomics data and STRING analysis, we demonstrated that the highly-expressed CD13 is also associated with proteins involved in the antigen presenting process, especially with CD1 proteins. Increasing expression of CD13 on dendritic cells while M. tuberculosis infection and enhancement of T cell activation after CD13 treated with anti-CD13 antibody indicates CD13 positively involved in the pathogenesis of M. tuberculosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12953-016-0095-8) contains supplementary material, which is available to authorized users.

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“…Ho et al conducted an experiment using magnetic nanoparticles and confocal microscopy to investigate the role of Aminopeptidase N (CD13), an ectoenzyme located in the outer membrane of a variety of cells, on the internalization and intracellular survival of Mycobacterium tuberculosis in monocytes. 50 M. tuberculosis was found to be capable of binding to either soluble or membranous CD13. Pretreatment of monocytes with anti-CD13 antibody (WM15 and WM47) reduced the number of intracellular M. tuber-culosis, thus lending support to a possible role of the enzyme in the pathogenesis.…”

Section: Tuberculosismentioning

confidence: 99%

Year in review 2014: Lung cancer, pleural diseases, respiratory infections and tuberculosis, bronchoscopic intervention and imaging

et al. 2015

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Aminopeptidase N facilitates entry and intracellular survival of Mycobacterium tuberculosis in monocytes

Abstract: CD13 acts as a receptor for M. tuberculosis on human monocytes. The molecule facilitates internalization, and interaction of CD13 with an anti-CD13 antibody reduces intracellular M. tuberculosis survival.

Cited by 7 publications

References 33 publications

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Analysis of the immune response of human dendritic cells to Mycobacterium tuberculosis by quantitative proteomics

Year in review 2014: Lung cancer, pleural diseases, respiratory infections and tuberculosis, bronchoscopic intervention and imaging

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