In this CETR program, 'Autophagy Modulators as Novel Broad-Spectrum Anti-infective Agents', we will discover, validate, and optimize novel broad-spectrum anti-infective agents. Our approach will be to enhance the anti-infective efficacy of a host pathway that is active against a wide range of NIAID priority pathogens. Autophagy and the function of autophagy-related genes (ATG genes) in resistance to infection represent such a pathway. Autophagy and ATG genes are central to immune defense against viruses, bacteria, and parasites including West Nile virus, chikungunya virus, norovirus, M. tuberculosis, S. aureus, T. gondii, L. monocytogenes, and S. typhimurium and therefore provide unique targets for the development of broad spectrum anti-infective agents. Autophagy is a cellular process in which cytoplasmic cargo, including pathogens and pathogen components, are captured within a double membrane-bound vesicle for delivery to the lysosome and degradation. ATG proteins can also play key roles in host defense via processes that do not require the autophagy pathway. In this CETR program we will develop small molecules that stimulate the activity of autophagy and/or ATG genes as broad-spectrum anti-infective agents. Our main deliverable will be semi-optimized lead compounds with protective effects in animals against a range of pathogens. We have already identified an autophagy-inducing peptide that protects mice against infection with diverse viruses, and have completed a high-density compound screen that has identified autophagy-inducing molecules that inhibit bacterial replication. We will develop these initial candidates, and will identify additional validated targets for further compound screens. Our team combines experts in the field including Drs. Skip Virgin, Beth Levine, Ramnik Xavier, and Stuart Schreiber, a group with an extensive history of collaboration and copublication. To accomplish our goals we will leverage the outstanding facilities and resources of the Broad Institute, the Massachusetts General Hospital, Washington University School of Medicine, and the University of Texas Southwestern Medical School. We will accomplish our goals through four Research Projects, an Administrative Core, and a Genetic and Pathway Analysis Core. Our Projects are: (1) Autophagy-Inducing Peptides and Target Identification for Treatment of Viruses (Levine);(2) Genes/Pathways for Autophagy dependent Inhibition of Bacterial Infection (Xavier);(3) Genes/Pathways for ATG Gene-dependent Inhibition of Virus and Parasite Infection (Virgin);and (4) Enhancing ATG-dependent Defense Against Pathogens with Therapeutic Lead Compounds (Schreiber). By focusing on autophagy and ATG genes, and using cutting edge technologies, our CETR team will optimize already existing therapeutic leads and provide a pipeline of novel targets for the development of a new class of broad-spectrum anti-infective medicines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Beanan, Maureen J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
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