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
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
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| 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 |
| Yokoyama, Christine C; Baldridge, Megan T; Leung, Daisy W et al. (2018) LysMD3 is a type II membrane protein without an in vivo role in the response to a range of pathogens. J Biol Chem 293:6022-6038 |
| Wilen, Craig B; Lee, Sanghyun; Hsieh, Leon L et al. (2018) Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 360:204-208 |
| Deretic, Vojo; Levine, Beth (2018) Autophagy balances inflammation in innate immunity. Autophagy 14:243-251 |
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