Adjunctive Host-Directed Therapy With Statins Improves Tuberculosis-Related Outcomes in Mice

J Infect Dis. 2020 Mar 16;221(7):1079-1087. doi: 10.1093/infdis/jiz517.


Background: Tuberculosis (TB) treatment is lengthy and complicated and patients often develop chronic lung disease. Recent attention has focused on host-directed therapies aimed at optimizing immune responses to Mycobacterium tuberculosis (Mtb), as adjunctive treatment given with antitubercular drugs. In addition to their cholesterol-lowering properties, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have broad anti-inflammatory and immunomodulatory activities.

Methods: In the current study, we screened 8 commercially available statins for cytotoxic effect, anti-TB activity, synergy with first-line drugs in macrophages, pharmacokinetics and adjunctive bactericidal activity, and, in 2 different mouse models, as adjunctive therapy to first-line TB drugs.

Results: Pravastatin showed the least toxicity in THP-1 and Vero cells. At nontoxic doses, atorvastatin and mevastatin were unable to inhibit Mtb growth in THP-1 cells. Simvastatin, fluvastatin, and pravastatin showed the most favorable therapeutic index and enhanced the antitubercular activity of the first-line drugs isoniazid, rifampin, and pyrazinamide in THP-1 cells. Pravastatin modulated phagosomal maturation characteristics in macrophages, phenocopying macrophage activation, and exhibited potent adjunctive activity in the standard mouse model of TB chemotherapy and in a mouse model of human-like necrotic TB lung granulomas.

Conclusions: These data provide compelling evidence for clinical evaluation of pravastatin as adjunctive, host-directed therapy for TB.

Keywords: Mycobacterium tuberculosis; antitubercular; host-directed therapy; standard first-line regimen; statin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Cell Survival
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Female
  • Granuloma
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Lung / drug effects
  • Lung / microbiology
  • Lung Diseases
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Mice
  • Mycobacterium tuberculosis / drug effects*
  • THP-1 Cells
  • Tuberculosis* / drug therapy
  • Tuberculosis* / microbiology
  • Vero Cells


  • Antitubercular Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors