Abstract
ABSTRACTTuberculosis (TB) treatment regimens are lengthy, causing non-adherence to treatment. Inadequate treatment can lead to relapse and the development of drug resistance TB. Furthermore, patients often exhibit residual lung damage even after cure, increasing the risk for relapse and development of other chronic respiratory illnesses. Host-directed therapeutics are emerging as an attractive means to augment the success of TB treatment. In this study, we used C3HeB/FeJ mice as an experimental model to investigate the potential role of rapamycin, a mammalian target of rapamycin inhibitor, as an adjunctive therapy candidate during the treatment of Mycobacterium tuberculosis infection with moxifloxacin. We report that administration of rapamycin with or without moxifloxacin reduced infection-induced lung inflammation, and the number and size of caseating necrotic granulomas. Results from this study strengthen the potential use of rapamycin and its analogs as adjunct TB therapy, and importantly underscore the utility of the C3HeB/FeJ mouse model as a preclinical tool for evaluating host-directed therapy candidates for the treatment of TB.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global burden
To confirm that rapamycin was active in the lungs of infected mice, lung tissue sections from Mtb-infected mice fed either eudragit or eRAPA diets for two weeks were stained with antibodies reactive against phosphorylated ribosomal protein S6. eRAPA treatment led to significant reduction in phospho-S6 expression in bronchial epithelial lining compared to control animals treated with eudragit (Supplementary Fig. 1)
This indicates that the mTORC1 pathway is inhibited in eRAPA-treated animals and confirms that rapamycin is active in Mtb-infected lungs
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global burden. Several drug regimens are available for the treatment of TB; the duration of the regimen is lengthy (6 months for drug-susceptible TB and more than 18 months for drug-resistant TB). These treatment modalities are often associated with severe side effects (Hosford et al, 2015, Sayada, 2010). Patients that complete treatment regimens successfully, frequently experience permanent lung damage due to aberrant inflammation in response to Mtb (Pasipanodya et al, 2010, Wallis and Hafner, 2015, Zumla et al, 2015). In patients who completed treatment for multidrug resistant disease (mean 21 months), FEV1 was only 63% of predicted value, indicating significant loss of lung function (de Vallière and Barker, 2004)
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