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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation
Journal of Infectious Diseases, Volume 209, No. 5, Year 2014
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Description
Background. Statins are cholesterol-lowering drugs, targeting HMG-CoA reductase, thereby reducing the risk of coronary disorders and hypercholesterolemia. However, they also can influence immunologic responses.Methods. Peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) were isolated from patients with familial hypercholesterolemia (FH) during statin therapy. After infection of cells with Mycobacterium tuberculosis, bacterial burden was determined. In vivo, mice were treated with statins before aerosol-based infection with M. tuberculosis and were monitored for disease progression.Results. PBMCs and MDMs from patients with FH receiving statin therapy were more resistant to M. tuberculosis infection, with reduced bacterial burdens, compared with those of healthy donors. Moreover, statin treatment in experimental murine M. tuberculosis infection studies increased host protection, with reduced lung burdens and improved histopathologic findings. Mechanistically, metabolic rescue experiments demonstrated that statins reduce membrane cholesterol levels, particularly by the mevalonate-isoprenoid arm of the sterol pathway. This promoted phagosomal maturation (EEA-1/Lamp-3) and autophagy (LC3-II), as shown by confocal microscopy and Western blot in macrophages. In addition, inhibitors of phagosome and autophagosome maturation reversed the beneficial effect of statins on bacterial growth.Conclusion. 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. © 2013 The Author.
Authors & Co-Authors
Parihar, Suraj P.
South Africa, Cape Town
University of Cape Town
South Africa
Institute of Infectious Diseases and Molecular Medicine
South Africa
Division of Immunology
Guler, Reto
South Africa, Cape Town
University of Cape Town
South Africa
Institute of Infectious Diseases and Molecular Medicine
South Africa
Division of Immunology
Khutlang, Rethabile
South Africa, Pretoria
The Council for Scientific and Industrial Research
Lang, Dirk M.
Unknown Affiliation
Hurdayal, Ramona
South Africa, Cape Town
University of Cape Town
South Africa
Institute of Infectious Diseases and Molecular Medicine
South Africa
Division of Immunology
Mhlanga, Musa M.
South Africa, Pretoria
The Council for Scientific and Industrial Research
Suzuki, Harukazu
Japan, Yokohama
Riken Yokohama Institute
Marais, Adrian David
South Africa, Cape Town
University of Cape Town
Brombacher, Frank
South Africa, Cape Town
University of Cape Town
South Africa
Institute of Infectious Diseases and Molecular Medicine
South Africa
Division of Immunology
Statistics
Citations: 243
Authors: 9
Affiliations: 5
Identifiers
Doi:
10.1093/infdis/jit550
ISSN:
00221899
Research Areas
Noncommunicable Diseases