Generating new antimicrobial agents has, most often, targeted individual organisms. Developing approaches that generate truly broad-spectrum anti-infective agents would be very valuable. One approach to accomplishing this goal would be to develop drugs that enhance the anti-infective efficacy of a host pathway that is active against a wide range of priority organisms. Autophagy and the function of autophagy-related genes {ATG genes) in resistance to infection represent such a pathway. Autophagy and ATG genes have extremely broad protective effects against viruses, bacteria, and parasites and therefore provide unique potential targets for the development of truly broad-spectrum anti-infective agents. Autophagy is a cellular process in which cytoplasmic cargo is captured within a double membrane-bound vesicle for delivery to the lysosome and degradation. We discovered that ATG proteins can also play key roles in host defense via processes that do not require the autophagy pathway. Herein, these mechanisms are called 'ATG gene dependent to distinguish them from 'autophagy-dependent'processes. ATG gene-dependent immunity is important both in vivo and in vitro to protect against infection with the two NIAID priority pathogens. Toxoplasma gondii and norovirus (NoV, a genus of the Caliciviridae). This demonstrates the broad physiologic importance of this novel mechanism of host defense. In Project 3 we will define the mechanisms of ATG gene-dependent immunity, and utilize this information to contribute to the development of broadspectrum anti-infective agents through this CETR program by: (i) participating in a high-density chemical compound screen to stimulate ATG gene-dependent immunity to T. gondii (Project 4, Aim 2), (ii) screening peptides and candidate therapeutics identified in Projects 1 and 4 for activity against T. gondii and both human and murine norovirus (HNoV, MNoV);and (iii) identifying candidate 'mechanism-defined'targets within the ATG gene-dependent immune process for additional chemical compound screens to be performed in Project 4. We will accomplish these goals through the following Specific Aims.
AIM 1 : Define the molecular mechanisms of ATG protein action n ATG gene-dependent immunity.
AIM 2 : Identify proteins and pathways involved In regulating ATG gene-dependent immunity.
AIM 3. Determine the physiologic importance of A7G gene-dependent immunity In vivo.
AIM 4. Determine the anti-infective potency of genes, autophagy-inducing peptides and candidate therapeutic compounds against NoV and T. gondii.

Public Health Relevance

Autophagy is a cellular process that participates in host resistance to West Nile virus, chikungunya virus, norovirus, M. tuberculosis, S. aureus, T. gondii, L. monocytogenes, and S. typhimurium. We have shown that stimulating autophagy can protect animals against diverse pathogens. Therefore we will develop methods to stimulate autophagy and the function of ATG genes to create truly broad-spectrum anti-infective agents

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LR-M (J1))
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Washington University
Saint Louis
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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

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