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

• Published in: The Journal of infectious diseases Vol. 209; no. 5; pp. 754 - 763
• Main Authors: Parihar, Suraj P., Guler, Reto, Khutlang, Rethabile, Lang, Dirk M., Hurdayal, Ramona, Mhlanga, Musa M., Suzuki, Harukazu, Marais, A. David, Brombacher, Frank
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-03-2014
• Subjects: Animals; Autophagy - drug effects; Bacteria; Bacteriology; Biological and medical sciences; Cholesterol - metabolism; Cholesterols; Drug Resistance, Bacterial - physiology; Fundamental and applied biological sciences. Psychology; Fungal infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia; Infections; Infectious diseases; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - microbiology; Macrophages; Macrophages - drug effects; Macrophages - microbiology; Medical sciences; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Phagosomes; Phagosomes - drug effects; Phagosomes - metabolism; Phagosomes - microbiology; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - metabolism; Tuberculosis - microbiology; Human; Rodentia; Statin derivative; Phagosome; Autophagy; Infection; Vertebrata; Mammalia; Treatment; Mycobacterium tuberculosis; Mouse; Mycobacteriales; Mycobacteriaceae; Bacteria; Actinomycetes; Antilipemic agent; Macrophage; Mice; Macrophages; Cholesterol
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit550

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 aerosolbased 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.