Adjunctive Host-Directed Therapy With Statins Improves Tuberculosis-Related Outcomes in Mice. (12th October 2019)

• Record Type: Journal Article
• Authors: Dutta, Noton K; Bruiners, Natalie; Zimmerman, Matthew D; Tan, Shumin; Dartois, Véronique; Gennaro, Maria L; Karakousis, Petros C
• Is Part Of: Journal of infectious diseases. Volume 221:Number 7(2020)
• Page Start: 1079
• Page End: 1087
• Publication Date: 2019-10-12
• Subjects: antitubercular -- host-directed therapy -- Mycobacterium tuberculosis -- standard first-line regimen -- statin; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiz517
• Languages: English
• ISSNs: 0022-1899

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.