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
Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Levine, Beth et al. (2017) Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16:487-511
Rocchi, Altea; Yamamoto, Soh; Ting, Tabitha et al. (2017) A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLoS Genet 13:e1006962
Baldridge, Megan T; Lee, Sanghyun; Brown, Judy J et al. (2017) Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus. J Virol 91:
Goodwin, Jonathan M; Dowdle, William E; DeJesus, Rowena et al. (2017) Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9. Cell Rep 20:2341-2356
Lassen, K G; Xavier, R J (2017) Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease. Mucosal Immunol 10:589-597
Franco, Luis H; Nair, Vidhya R; Scharn, Caitlyn R et al. (2017) The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. Cell Host Microbe 22:421-423
Li, Yue; Zhao, Yuting; Su, Minfei et al. (2017) Structural insights into the interaction of the conserved mammalian proteins GAPR-1 and Beclin 1, a key autophagy protein. Acta Crystallogr D Struct Biol 73:775-792
Köster, Stefan; Upadhyay, Sandeep; Chandra, Pallavi et al. (2017) Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proc Natl Acad Sci U S A 114:E8711-E8720
Bartolomeo, Rosa; Cinque, Laura; De Leonibus, Chiara et al. (2017) mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Invest 127:3717-3729
Murano, Tatsuro; Najibi, Mehran; Paulus, Geraldine L C et al. (2017) Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo. Sci Rep 7:13938

Showing the most recent 10 out of 80 publications