Description

mTOR Inhibition as a Potential Host-Directed Therapeutic Target in Pathologically Distinct Murine Models of Tuberculosis

Despite recent advances in TB drug development, first-line treatment for drug-susceptible TB still consists of an extended regimen comprising four drugs: isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months, followed by isoniazid and rifampicin for another 4 months (RHZE). Treatments for multidrug- and extensively drug-resistant (MDR/XDR) TB are more complex and lengthy, although the novel short-course regimen of bedaquiline, pretomanid and linezolid (BPaL) has recently shown promising efficacy against XDR-TB and treatment-intolerant MDR-TB. Efforts to develop more effective and shorter-course therapies for TB have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the endogenous host response to infection, thereby improving the host immune defenses against the pathogen, reducing the duration of antibacterial therapy and/or the amount of lung damage sustained. HDT has already shown promise by demonstrating reduced lung pathology in mouse models of pulmonary TB.
 A target of interest for HDT in TB is autophagy, an intracellular homeostatic process that degrades damaged cellular components and organelles during cellular stress via lysosomal degradation. Autophagy is also part of the innate immune response involved in eliminating intracellular pathogens. Additionally, it is involved in adaptive immunity; facilitating antigen presentation, which eventually leads to granuloma formation. Mycobacterium tuberculosis impedes the host cells’ ability to complete autophagy via the modulation of mammalian target of rapamycin (mTOR); therefore, utilizing an mTOR inhibitor could modulate this effect on mTOR and provide a novel HDT for TB.
 mTOR is a serine/threonine kinase and exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin only partially inhibits the mTORC1 complex, however; it is hypothesized that mTOR kinase inhibitors blocking both mTORC1 and mTORC2 signaling could have expanded therapeutic potential. 
 Herein we compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, against murine TB, as monotherapies or when added to RHZE or BPaL. Beginning 6 weeks after low-dose aerosol infection with Mtb HN878, BALB/c and C3HeB/FeJ mice received rapamycin (4 mg/kg IP, q3d) or CC214-2 (30 mg/kg PO, qd) alone or in combination with RHZE or BPaL. Control mice were untreated or received RHZE or BPaL. Rapamycin alone promoted more Mtb multiplication (BALB/c mice) and death (C3HeB/FeJ mice) compared to no treatment, whereas CC214-2 alone did not. Neither mTOR inhibitor in combination with BPaL or RHZE significantly affected lung CFU counts in mice. However, in relapse analyses, BALB/c mice treated with BPaL and RHZE had significantly more relapses when dosed with rapamycin compared to those dosed with CC214-2 or no mTOR inhibitor. C3HeB/FeJ mice treated with BPaL and RHZE and dosed with CC214-2 had significantly fewer relapses when compared to dosing with rapamycin and, in RHZE-treated mice, had fewer relapses when compared to no mTOR inhibitor. These results suggest that mTOR kinase inhibitors such as CC214-2 may be a safer and more effective mTOR inhibitor candidate for HDT than rapamycin and that CC214-2 may have the potential to shorten the duration of treatment with RHZE.