Autophagy is an evolutionarily conserved cellular pathway in which cytoplasmic constituents including organelles and microbes or microbial constituents called “cargo” are enveloped in a double membrane-bound vesicle, the autophagosome, which fuses to the lysosome to create the autolysosome. Cargo is then degraded by lysosomal enzymes. All eukaryotic cells perform autophagy, which plays a key role in a range of cellular and physiologic processes including resistance to infection and regulation of immunity. Autophagy can capture either whole pathogens or pathogen components as cargo, resulting in killing of pathogens or clearance of pathogen-encoded molecules (Fig. 4).
Degradative autophagy can target intracellular pathogens, including Mtb, to the lysosome for destruction. While Mtb can block autophagy, we have shown that degradative autophagy can be induced to control Mtb infection and have identified mechanisms involved in triggering degradative autophagy during Mtb infection. We identified key roles for the cytoplasmic DNA sensor cGAS and its downstream signaling partner Sting in autophagy initiation and roles for the ubiquitin ligases Smurf1 and Parkin in targeting Mtb for degradation. An important validation of our approach to increase degradative autophagy and its physiologic importance is that autophagy-enhancing compounds reduce Mtb replication. For example, a peptide developed to enhance autophagy also enhances killing of Mtb.
On the basis of our previous work, we hypothesized that molecules that enhance autophagy could be advanced as host-directed therapies for Mtb infection. To that end, in a collaboration with labs at UTSW, Washington University of St. Louis, Harvard/Broad Institute, Scripps Institute and Vir pharmaceuticals, we are identifying new targets for enhancing autophagy, and developing established molecules from high-throughput screens. We anticipate that this work will lead to novel therapeutic approaches towards the treatment of Mtb and other important pathogens.