The process of autophagy in response to bacteria, viruses and other pathogens is a critical feature of innate immunity and the overall host response to potential pathogens. The overall goal of this CETR is to define the shared and distinct mechanisms of autophagy and autophagy-protein-dependent immune responses to different classes of pathogens. These include Sindbis virus and herpes simplex virus, intracellular bacteria that are degraded by classical autophagy (including Salmonella typhimurium and Listeria monocytogenes) as well as other viruses (murine norovirus) and the protozoan parasite, T. gondii, that are controlled by nondegradative functions of autophagy proteins. (For brevity, these distinct processes will be collectively referred to as """"""""pathogen-induced autophagy."""""""") The goal of Core B is to provide the analytic and chemical biology capabilities that will be critical to all four Projects as they systematically identify pathway components important for pathogen-induced autophagy, and devise therapeutics that target host autophagy, and are active against a variety of unrelated pathogens. Core B will integrate complementary datasets from a systematic, forward genetic approach (genome-wide RNAi screen) as well as a more targeted chemical biology approach (cell perturbation by compounds with known targets). Core B will also perform Landmark 1000 analysis of promising RNAi knockdowns, and chemical compounds identified by the individual Projects through their screens. The Core Director and Co-Director have a record of collaboration and extensive experience performing the analyses that will be provided in order to extract mechanistic insights into pathogen-induced autophagy and derive functional connections between genes and chemical compounds that can modulate pathogen-induced autophagy. This Core leverages extensive chemical biology/chemical perturbation and analytic resources available at IVIGH and the Broad Institute. Equally important, the Core builds upon existing collaborations and a history of co-publication among the Project Pi's, the Core Director and Co-Director, team members at the Broad Institute, and the CETR Project Pis

Public Health Relevance

Autophagy directs proteins, organelles and pathogens to the lysosome for degradation, and has been implicated in the control of a broad array of pathogens as well as several human diseases (such as Crohn's disease, neurodegenerative disease, cancer, aging and heart disease). Extensive screening data and protein interaction data indicate that the network of autophagy proteins and autophagy protein-dependent cellular processes is highly complex. Core B will integrate large experimental and external datasets to help this CETR identify autophagy mechanisms that are shared across many pathogens, and that could be therapeutically targeted to create novel anti-infective agents with activity against multiple unrelated emerging and re-emerging pathogens

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109725-01
Application #
8655108
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$401,637
Indirect Cost
$34,079
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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