Infection of A549 human type II epithelial cells with Mycobacterium tuberculosis induces changes in mitochondrial morphology, distribution and mass that are dependent on the early secreted antigen, ESAT-6

Fine-Coulson, Kari; Giguère, Steeve; Quinn, Frederick D.; Reaves, Barbara J.

doi:10.1016/j.micinf.2015.06.003

Cited by 43 publications

(23 citation statements)

References 39 publications

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“…We experienced difficulties in staining these cells due to the presence of these lipid bodies. As shown in earlier studies (Fine-Coulson et al, 2015 ), we also observe that M.tb infection alone affected mitochondrial morphology as compared to uninfected cells (Figures 2A,B ), however, mitochondria in cholesterol treated infected cells were distinctly solitary, swollen, and spherical in shape (Figure 2B lower panel, column ii) representing extreme stress that may lead to mitochondrial dysfunction.…”

Section: Discussionsupporting

confidence: 88%

Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia

Asalla

Mohareer

Banerjee

2017

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis (M.tb) infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses. While high cholesterol levels are clinically proven condition for perturbations in cardiac health, a significant fraction of population these days suffer from borderline risk cholesterol profiles. This apparently healthy population is susceptible to various health risks placing them in the “pre-disease” range. Our study focuses on determining the role of such asymptomatic dyslipidemia as a potential risk factor for susceptibility to TB persistence. Macrophages exposed to sub-pathological levels of cholesterol for chronic period, besides impaired release of TNF-α, could not clear intracellular pathogenic mycobacteria effectively as compared to the unexposed cells. These cells also allowed persistence of opportunistic mycobacterial infection by M. avium and M. bovis BCG, indicating highly compromised immune response. The cholesterol-treated macrophages developed a foamy phenotype with a significant increase in intracellular lipid-bodies prior to M.tb infection, potentially contributing to pre-disease state for tuberculosis infection. The foamy phenotype, known to support M.tb infection, increased several fold upon infection in these cells. Additionally, mitochondrial morphology and function were perturbed, more so during infection in cholesterol treated cells. Pharmacological supplementation with small molecule M1 that restored mitochondrial structural and functional integrity limited M.tb survival more effectively in cholesterol exposed macrophages. Mechanistically, M1 molecule promoted clearance of mycobacteria by reducing total cellular lipid content and restoring mitochondrial morphology and function to its steady state. We further supported our observations by infection assays in PBMC-derived macrophages from clinically healthy volunteers with borderline risk cholesterol profiles. With these observations, we propose that prolonged exposure to sub-pathological cholesterol can lead to asymptomatic susceptibility to M.tb persistence. Use of small molecules like M1 sets yet another strategy for host-directed therapy where re-functioning of mitochondria in cholesterol abused macrophages can improve M.tb clearance.

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Section: Discussionsupporting

confidence: 88%

Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia

Asalla

Mohareer

Banerjee

2017

Front. Cell. Infect. Microbiol.

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“…Infection with E coli-LF82 evoked a time-and dose-dependent fragmentation of mitochondria in gut-derived epithelia. The bacterial pathogens Listeria monocytogenes, Shigella flexneri, Mycobacterium tuberculosis, and Vibrio cholerae all cause mitochondrial fragmentation, [38][39][40][41] and this often was accompanied by reduced DJ m .…”

Section: Discussionmentioning

confidence: 99%

Crohn’s Disease Pathobiont Adherent-Invasive E coli Disrupts Epithelial Mitochondrial Networks With Implications for Gut Permeability

Mancini

Rajeev

Jayme

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…It is composed of type I and type II pneumocytes, which form a cell layer that provides a barrier function (Lin et al, 1998 ; Chuquimia et al, 2013 ). Increasing evidence implicated that alveolar epithelium, particularly type II pneumocyte, plays an important role in both host cell defense and bacterial dissemination (Xiong et al, 2014 ; Fine-Coulson et al, 2015 ; Ryndak et al, 2015 ). Mycobacterium smegmatis ( MS ) takes advantage of macropinocytosis for entry into epithelial cells, and internalized MS are killed by A549 cells (Garcia-Perez et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Heparin-binding Hemagglutinin of Mycobacterium tuberculosis Is an Inhibitor of Autophagy

Zheng

Zhou

et al. 2017

Front. Cell. Infect. Microbiol.

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Airway epithelial cell is often the initial site of attack by pathogens, and cell death is commonly caused by internalization of Mycobacterium tuberculosis (Mtb). However, the mechanism of interaction between epithelial cells and Mtb is not well understood. In this study, we investigated the role of the heparin-binding hemagglutinin (HBHA) protein of Mtb in the function of epithelial cells. In particular, the autophagy of A549 cells was determined based on microtubule-associated protein 1 light chain 3 alpha (LC3) activity. Autophagosome formation was detected by Monodansylcadaverine (MDC) staining and immune fluorescence staining of LC3. Autophagy could be significantly suppressed by HBHA protein. In addition, the LDH assay results showed that HBHA treatment could induce death on A549 cells. To explore the form of cell death, we detected the activity of caspase-3 and LDH release of A549 cells in the presence or absence of caspase inhibitor Z-VAD-FMK. Results demonstrated that HBHA treatment could induce apoptosis of A549 cells. To further confirm these results, we constructed the recombinant Mycobacterium smegmatis (MS) expressing HBHA (rMS-HBHA) and explored the influence of rMS-HBHA on the function of A549 cells. rMS-HBHA infection significantly inhibited LC3 expression and the maturation of autophagosomes in A549 cells. Subsequently, we infected A549 cells with MS and detected the viability of intracellular MS by CFU counts. rMS-HBHA showed higher survival and replication capacity in A549 cells than those of the wild-type MS. Finally, infection of A549 cells with rMS-HBHA caused further apoptosis. These findings suggested that rMS-HBHA could inhibit autophagy, promote its survival and replication within A549 cells, and subsequently induce apoptosis on infected cells to facilitate infection.

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Infection of A549 human type II epithelial cells with Mycobacterium tuberculosis induces changes in mitochondrial morphology, distribution and mass that are dependent on the early secreted antigen, ESAT-6

Cited by 43 publications

References 39 publications

Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia

Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia

Crohn’s Disease Pathobiont Adherent-Invasive E coli Disrupts Epithelial Mitochondrial Networks With Implications for Gut Permeability

Heparin-binding Hemagglutinin of Mycobacterium tuberculosis Is an Inhibitor of Autophagy

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