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

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.

Anti-tuberculous Effects of Statin Therapy: A Review of Literature

“…Among all statins, pravastatin exhibited the most potent adjunctive activity with the least toxicity by modulating phagosomal maturation characteristics in THP-1 macrophages. These observations concluded that pravastatin can be an attractive candidate for host-directed, adjunctive TB therapy [13]. All in vitro studies are summarized in Table 1.…”

“…To determine whether statins can enhance the activity of anti-TB drugs against intracellular bacilli in macrophages, Dutta et al conducted another study in 2019 [13]. They performed experiments with the M. TB H37Rv and THP-1 macrophages infected at MOI of 20.…”

“…In 2019, Dutta et al conducted another experiment on female C3HeB/FeJ mice, five to six weeks of age to determine the anti-TB activity of statins in mice [13]. The mice were inoculated by aerosols of M. TB H37Rv calibrated to deliver ~10 2 CFU/mouse lung.…”

“…Classic first-line TB treatment consists of four drugs: rifampicin, isoniazid, pyrazinamide, and ethambutol. Statins, as an adjunct, have also been found to increase the effects of first-line TB drugs [13].…”

The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis

“…For example, their use has been explored against multisystem microbial infections, such as sepsis and pneumonia, and in non-infectious pathologies, such as autoimmune and inflammatory diseases (18-20). In regard to tuberculosis, statins exhibit anti-tubercular activity in murine and human macrophages infected ex vivo (9, 12, 13), display immunomodulatory effects in ex vivo infected human peripheral blood cells (13), and shorten the duration of antibiotic treatment in M. tuberculosis -infected mice (10, 11). Previous work (9) found a reduction in M. tuberculosis burden in murine macrophages by high doses of statins that inhibited both the cholesterol- and isoprenoid-forming branches of the mevalonate pathway.…”