Statin Therapy Reduces the Mycobacterium tuberculosis Burden in Human Macrophages and in Mice by Enhancing Autophagy and Phagosome Maturation

Parihar, Suraj P.; Guler, Reto; Khutlang, Rethabile; Lang, Dirk; Hurdayal, Ramona; Mhlanga, Musa M.; Suzuki, Harukazu; Marais, A. David; Brombacher, Frank

doi:10.1093/infdis/jit550

Cited by 255 publications

(260 citation statements)

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“…It has been recently documented that statins also have immunomodulatory and anti-inflammatory effects with reports of reduced mortality in patients with bacteremia (Kwak et al, 2000;Liao and Laufs, 2005;Tleyjeh et al, 2009;Parihar et al, 2014). In TB mice models, treatment with statins significantly reduced the bacterial load and the pulmonary pathological effects of TB infection (Parihar et al, 2014).…”

Section: Arg677trp (C2029t)mentioning

confidence: 99%

“…It was further shown in TB-infected macrophages and in mice models that treatment with statins improves the efficacy of first-line TB drug regimens and of rifampicin alone (Lobato et al, 2014;Skerry et al, 2014). It was demonstrated that statins improve bacterial clearance by the host and improve the efficacy of TB drugs by promoting autophagy through inhibition of the HMG-CoA reductase pathway (Parihar et al, 2014). Furthermore, there are some reports claiming that statins also enhance autophagy in an mTOR-dependent way by inhibiting the RAC1-mTOR signaling pathway (Wei et al, 2013).…”

Section: Arg677trp (C2029t)mentioning

confidence: 99%

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Autophagy in the Fight Against Tuberculosis

Bento

Empadinhas

Mendes

2015

DNA and Cell Biology

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Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB. Mycobacterium tuberculosis: Biology and Infection

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Section: Arg677trp (C2029t)mentioning

confidence: 99%

Section: Arg677trp (C2029t)mentioning

confidence: 99%

Autophagy in the Fight Against Tuberculosis

Bento

Empadinhas

Mendes

2015

DNA and Cell Biology

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“…Mtb (H37Rv) was grown to log phase in 7H9 complete media, and stocks were prepared for infections via an intranasal route as described previously. 50 Bacterial loads in lungs and spleen of Mtb-infected mice were determined at indicated time points after infection. Briefly, organs from killed mice were removed aseptically, weighed, and homogenized in 0.04% Tween-80.…”

Section: Methodsmentioning

confidence: 99%

“…Murine BMDMs and human MDMs were generated as previously described. 50 Macrophages were pretreated with either Ox-LDLs (100 mg ml À 1 ), native-LDLs (125 mg ml À 1 ), oleic acid (500 mM), palmitic acid (500 mM), or left untreated overnight. Cells were then infected in the presence of treatment(s) with Mtb (H37Rv, unless otherwise indicated) with multiplicity of infection of 2.…”

Section: Methodsmentioning

confidence: 99%

“…Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis was performed as previously described. 50 Briefly, macrophages (3 Â 10 6 ) were infected with Mtb at multiplicity of infection of 2 for 4 h. Cells were washed and then lysed with ice-cold RIPA buffer containing protease inhibitors for 30 min at 4 1C. Total cell lysates were analyzed for protein contents using BCA assay (ThermoFisher, Waltham, MA).…”

Section: Methodsmentioning

confidence: 99%

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Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

et al. 2018

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We previously demonstrated that protein kinase C-δ (PKCδ) is critical for immunity against Listeria monocytogenes, Leishmania major, and Candida albicans infection in mice. However, the functional relevance of PKCδ during Mycobacterium tuberculosis (Mtb) infection is unknown. PKCδ was significantly upregulated in whole blood of patients with active tuberculosis (TB) disease. Lung proteomics further revealed that PKCδ was highly abundant in the necrotic and cavitory regions of TB granulomas in multidrug-resistant human participants. In murine Mtb infection studies, PKCδ−/− mice were highly susceptible to tuberculosis with increased mortality, weight loss, exacerbated lung pathology, uncontrolled proinflammatory cytokine responses, and increased mycobacterial burdens. Moreover, these mice displayed a significant reduction in alveolar macrophages, dendritic cells, and decreased accumulation of lipid bodies (lungs and macrophages) and serum fatty acids. Furthermore, a peptide inhibitor of PKCδ in wild-type mice mirrored lung inflammation identical to infected PKCδ−/− mice. Mechanistically, increased bacterial growth in macrophages from PKCδ−/− mice was associated with a decline in killing effector functions independent of phagosome maturation and autophagy. Taken together, these data suggest that PKCδ is a marker of inflammation during active TB disease in humans and required for optimal macrophage killing effector functions and host protection during Mtb infection in mice.

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Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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Statin Therapy Reduces the Mycobacterium tuberculosis Burden in Human Macrophages and in Mice by Enhancing Autophagy and Phagosome Maturation

Abstract: These results suggest that statin-mediated reduction in cholesterol levels within phagosomal membranes counteract M. tuberculosis-induced inhibition of phagosomal maturation and promote host-induced autophagy, thereby augmenting host protection against tuberculosis.

Cited by 255 publications

References 38 publications

Autophagy in the Fight Against Tuberculosis

Autophagy in the Fight Against Tuberculosis

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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