Autophagy is a conserved homeostatic process by which cells degrade and recycle cytoplasmic content and organelles. Recent work has identified a critical role for autophagy in host defense against intracellular bacteria, viruses, and parasites. Thus, new therapeutic approaches aimed at augmenting host autophagy bear potential to combat a diversity of human pathogens for which current treatment strategies are inadequate. While significant progress has been made in identifying and defining the roles of autophagy related (ATG) genes, it is clear that they are insufficient to account for the exquisite regulation of microbialhost cell interactions. The overarching focus of this application is to (1) define a systems-level understanding of autophagy by identifying genes and pathways that are essential for antibacterial autophagy and (2) leverage these insights to develop/test lead compounds that enhance autophagy and function as broadspectrum anti-infective agents.
In Aim 1, we will identify candidate host genes and pathways that regulate and serve as effectors in antibacterial autophagy using a genome-wide siRNA screen. These experiments include screening for genes that affect autophagy of NIAID Category B/C pathogens: Salmonella Typhimurium, Mycobacterium tuberculosis, and Listeria monocytogenes.
In Aim 2, we will identify the mechanism of action of candidate genes that function as effectors and/or regulators of antibacterial autophagy; this work will identify/prioritize new target pathways in which to screen for small molecules that augment autophagy.
In Aim 3, we will determine the efficacy of existing (and future) lead compounds/peptides as broad-spectrum anti-infective agents in models of bacterial infection. Collectively, these studies will provide insights into key cellular mechanisms that regulate antibacterial autophagy and facilitate the development of new therapeutic approaches for the treatment of high priority infectious diseases. Design, execution and analysis of experiments will require input from Core B. Moreover, through interactions with the other projects in this proposal (led by Drs. Levine, Schreiber, and Virgin), we expect these efforts to produce an autophagy connectivity network integrated across multiple pathogens and to identify lead compounds with broad-spectrum anti-infective activity.
An understanding of the mechanisms that protect against bacterial infections is necessary to identify new treatments. Autophagy plays a crucial role in host defense against a broad range of pathogens, including bacteria. However, the mechanisms of autophagy in bacterial control are poorly understood. This project will lead to new understandings of the mechanisms underlying autophagy. Moreover, it will exploit these insights to develop therapeutic approaches to combat infectious disease by promoting autophagy.
| Theisen, Derek J; Davidson 4th, Jesse T; Briseño, Carlos G et al. (2018) WDFY4 is required for cross-presentation in response to viral and tumor antigens. Science 362:694-699 |
| Mohanan, Vishnu; Nakata, Toru; Desch, A Nicole et al. (2018) C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Science 359:1161-1166 |
| Chiang, Wei-Chung; Wei, Yongjie; Kuo, Yi-Chun et al. (2018) High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding. ACS Chem Biol 13:2247-2260 |
| Peraro, Leila; Deprey, Kirsten L; Moser, Matthew K et al. (2018) Cell Penetration Profiling Using the Chloroalkane Penetration Assay. J Am Chem Soc 140:11360-11369 |
| Nelson, Christopher A; Wilen, Craig B; Dai, Ya-Nan et al. (2018) Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor. Proc Natl Acad Sci U S A 115:E9201-E9210 |
| Fernández, Álvaro F; Sebti, Salwa; Wei, Yongjie et al. (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558:136-140 |
| Radke, Joshua B; Burrows, Jeremy N; Goldberg, Daniel E et al. (2018) Evaluation of Current and Emerging Antimalarial Medicines for Inhibition of Toxoplasma gondii Growth in Vitro. ACS Infect Dis 4:1264-1274 |
| Thackray, Larissa B; Handley, Scott A; Gorman, Matthew J et al. (2018) Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections. Cell Rep 22:3440-3453.e6 |
| Lassen, Kara G; Xavier, Ramnik J (2018) Mechanisms and function of autophagy in intestinal disease. Autophagy 14:216-220 |
| Graham, Daniel B; Luo, Chengwei; O'Connell, Daniel J et al. (2018) Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes. Nat Med 24:1762-1772 |
Showing the most recent 10 out of 97 publications
