Atorvastatin accelerates <i>Mycobacterium tuberculosis</i> clearance in pulmonary TB: a randomised phase IIA trial

Adewole, O O; Omotoso, B.; Ogunsina, Modupe Arinola; Aminu, A.; Odeyemi, A O; Awopeju, O.F.; Ayoola, Oluwagbemiga Oluwole; Adedeji, T; Sogaolu, Olumide M.; Adewole, T O; Jiya, E; Andero, V; Obaseki, D; Akintomide, Anthony Olubunmi; Erhabor, G E

doi:10.5588/ijtld.22.0548

Cited by 7 publications

(3 citation statements)

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“…Furthermore, as FFM do not respond to signals for epithelioid transformation, these macrophages could reach the caseum of granulomas. It would explain why statins regress tuberculoid lesions in a mouse model with human-like necrotic pulmonary granulomas [89], and also accelerate Mycobacterium tuberculosis clearance in pulmonary TB in humans [90]. However, our findings also alert on the potential of statins to exacerbate pre-existing inflammatory diseases linked to a sterile activation of the NLRP3 inflammasome [91], as observed in diabetes mellitus type I patients [92].…”

Section: Discussionmentioning

confidence: 57%

Fluvastatin Converts Human Macrophages into Pro-inflammatory Foam Cells with Therapeutic Potential in Tuberculosis

Montero-Vega,

Matilla,

Bazán

et al. 2023

Preprint

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Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients from developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMC) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMC, most monocytes/macrophages became foamy cells that overproduce NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMC were exposed to Mtb, a subset of macrophages quickly captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFN-gamma. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria to degrade them, markedly activated caspase-1 and elicited a potent IFNgamma/cytotoxic response. In rabb-gammaits immunized with the same bacteria, fluvastatin therapy increased the tuberculin test response. We conclude that statins enhance macrophage effectiveness to control Mtb supported by adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.

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Section: Discussionmentioning

confidence: 57%

Fluvastatin Converts Human Macrophages into Pro-inflammatory Foam Cells with Therapeutic Potential in Tuberculosis

Montero-Vega,

Matilla,

Bazán

et al. 2023

Preprint

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“…Together, our in vitro and in vivo results suggest that in hypercholesterolemic patients receiving statin therapy, these drugs could help FMs to activate an efficient IFNγ/cytotoxic response that controls the pathogen at the earliest stages of infection, thus preventing their conversion to LL-FMs and the development of active tuberculosis. Furthermore, as FFMs do not respond to signals for epithelioid transformation, these macrophages could reach the caseum of granulomas, which could also explain why statins regress tuberculoid lesions in a mouse model with human-like necrotic pulmonary granulomas [ 90 ], and also accelerate Mycobacterium tuberculosis clearance in pulmonary TB in humans [ 91 ]. Findings in the present work may support the use of statins as adjuvant drugs in treating tuberculosis but, they also alert on the potential of these drugs to exacerbate pre-existing inflammatory diseases linked to a sterile activation of the NLRP3 inflammasome [ 92 ], for example, as observed in diabetes mellitus type I [ 93 ].…”

Section: Discussionmentioning

confidence: 99%

Fluvastatin Converts Human Macrophages into Foam Cells with Increased Inflammatory Response to Inactivated Mycobacterium tuberculosis H37Ra

Montero-Vega,

Matilla,

Bazán

et al. 2024

Cells

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Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMCs) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMCs, most monocytes/macrophages became foamy cells that overproduced NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMCs were exposed to Mtb H37Ra, a small subset of macrophages captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFNγ. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria, degraded them, markedly activated caspase-1 and elicited a potent IFNγ/cytotoxic response. In rabbits immunized with the same bacteria, fluvastatin increased the tuberculin test response. We conclude that statins may enhance macrophage efficacy to control Mtb, with the help of adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.

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“…Additionally, the open-label ATORTUB clinical trial (NCT04721795) randomized participants to receive standard-of-care antibiotic therapy with or without atorvastatin. Following 2 months of treatment, patients randomized to receive atorvastatin had an increased rate of sputum culture conversion and reduced chest x-ray severity scores, demonstrating the potential of targeting cholesterol as host-directed therapy [ 25 ] .…”

Section: Cholesterol Fuels M Tuberculosis Pathogen...mentioning

confidence: 99%

The role of cholesterol and its oxidation products in tuberculosis pathogenesis

Roth,

Philips,

Chandra

2024

Immunometabolism

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Mycobacterium tuberculosis causes tuberculosis (TB), one of the world’s most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.

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Atorvastatin accelerates Mycobacterium tuberculosis clearance in pulmonary TB: a randomised phase IIA trial

Cited by 7 publications

References 0 publications

Fluvastatin Converts Human Macrophages into Pro-inflammatory Foam Cells with Therapeutic Potential in Tuberculosis

Fluvastatin Converts Human Macrophages into Pro-inflammatory Foam Cells with Therapeutic Potential in Tuberculosis

Fluvastatin Converts Human Macrophages into Foam Cells with Increased Inflammatory Response to Inactivated Mycobacterium tuberculosis H37Ra

The role of cholesterol and its oxidation products in tuberculosis pathogenesis

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