Adjunctive host-directed therapy with statins improves tuberculosis-related outcomes in mice

Noton K. Dutta, Natalie Bruiners, Matthew D. Zimmerman, Shumin Tan, Véronique Dartois, Maria L. Gennaro, Petros C. Karakousis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1079-1087
Number of pages9
JournalJournal of Infectious Diseases
Volume221
Issue number7
DOIs
StatePublished - 2020

Keywords

  • Antitubercular
  • Host-directed therapy
  • Mycobacterium tuberculosis
  • Standard first-line regimen
  • Statin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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