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

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 #
8655105
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
$774,740
Indirect Cost
$65,737
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Xu, Xiaojin; Araki, Koichi; Li, Shuzhao et al. (2014) Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol 15:1152-61
Choi, Jayoung; Park, Sunmin; Biering, Scott B et al. (2014) The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40:924-35
Karst, Stephanie M; Wobus, Christiane E; Goodfellow, Ian G et al. (2014) Advances in norovirus biology. Cell Host Microbe 15:668-80