Advancing Apoptosis-Inducing Agents as Host-Directed Therapy for TB

About This Grant

Mycobacterium tuberculosis (Mtb) is known to subvert host immune responses to establish infection and cause tuberculosis (TB) disease. Thus, boosting host immune responses via host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. Apoptosis is an evolutionarily conserved pathway for genetically programmed cell death, and the successful execution of macrophage apoptosis following infection with Mtb serves as an important innate immune defense. However, Mtb has evolved virulence strategies to subvert macrophage apoptosis and induce necrosis, thereby promoting its survival and dissemination of infection. Mitochondria mediate intrinsic apoptosis and can participate in the amplification of extrinsic apoptosis signaling, as well as contribute to alternate cell death modalities. Previously, we observed alterations to canonical apoptosis activation in Mtb-infected macrophages, manifested by mitochondrial translocation of anti-apoptotic XIAP in parallel with incomplete mitochondrial apoptotic pore formation. Our data are consistent with those of other groups suggesting that Mtb interferes with the central process of intrinsic apoptosis signaling, namely mitochondrial outer membrane permeabilization (MOMP). In support of an apoptosis-inducing HDT approach for TB, we and others found that promotion of the intrinsic apoptosis pathway through pharmacological inhibition of the anti-apoptotic factors MCL-1 and BCL-2 reduces intracellular Mtb growth in macrophages and in vitro granulomas. We have shown that adjunctive treatment with an activator of caspase-3 enhances the bactericidal and sterilizing activities of the first-line anti-TB regimen in a murine TB model. Recently, we found that adjunctive treatment with a clinical-stage inhibitor of BCL-2/BCL-XL enhances the bactericidal activity of the first-line antitubercular regimen and decreases the size and necrosis of lung lesions in a murine model of human TB-like pathology. In addition, enhancement of both extrinsic and intrinsic apoptosis through inhibition of inhibitor of apoptosis (IAP) family proteins augments the clearance of Mtb in the lungs of chronically infected mice. In the current proposal, we will identify apoptosis-inducing HDT agents of clinical relevance that can be exploited to enhance macrophage-based clearance of Mtb. We will employ a combination of targeted genetic and pharmacological approaches and integrate state-of-the-art knowledge on MOMP regulation to comprehensively characterize mechanisms of action involved in their antitubercular HDT activity. Selected apoptosis-inducing HDT agents will be tested for their adjunctive ability to shorten the duration of curative TB treatment in a clinically- relevant animal model. Our team combines significant expertise in TB pathogenesis, the mechanistic investigation of apoptosis and alternative cell death modalities, single-cell microscopy and in vivo imaging, and HDT development for TB. Our findings are expected to yield novel HDTs that can be tested in clinical trials for their potential to shorten the duration of curative treatment and improve long-term lung function in patients with drug-susceptible and drug-resistant TB.