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

Author:

Dutta Noton K1,Bruiners Natalie2,Zimmerman Matthew D2,Tan Shumin3,Dartois Véronique2,Gennaro Maria L2,Karakousis Petros C14

Affiliation:

1. Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

2. Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, New Jersey, USA

3. Tufts University School of Medicine, Department of Molecular Biology and Microbiology, Boston, Massachusetts, USA

4. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Abstract

Abstract 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.

Funder

Bill and Melinda Gates Foundation

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

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