TY - JOUR
T1 - Adjunctive host-directed therapy with statins improves tuberculosis-related outcomes in mice
AU - Dutta, Noton K.
AU - Bruiners, Natalie
AU - Zimmerman, Matthew D.
AU - Tan, Shumin
AU - Dartois, Véronique
AU - Gennaro, Maria L.
AU - Karakousis, Petros C.
N1 - Publisher Copyright:
© The Author(s) 2019.
PY - 2020/3/16
Y1 - 2020/3/16
N2 - 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.
AB - 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.
KW - Antitubercular
KW - Host-directed therapy
KW - Mycobacterium tuberculosis
KW - Standard first-line regimen
KW - Statin
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U2 - 10.1093/infdis/jiz517
DO - 10.1093/infdis/jiz517
M3 - Article
C2 - 31605489
AN - SCOPUS:85080029379
SN - 0022-1899
VL - 221
SP - 1079
EP - 1087
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 7
ER -