title: Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component.
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Rethabile
authors.initials: R
authors.lastname: Khutlang
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Lang
authors.forename: Ramona
authors.initials: R
authors.lastname: Hurdayal
authors.forename: Musa M
authors.initials: MM
authors.lastname: Mhlanga
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010588:Phagosomes / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol
keywords: Cholesterol; Human; Macrophages; Mice; Mycobacterium tuberculosis