In addition to traditional antimicrobials, targeting host defense pathways is an attractive strategy to limit the adverse effect of bacterial infection. One such pathway that has received considerable attention is autophagy, a process by which cellular constituents are sequestered in a double-membrane vesicle that is subsequently targeted to the lysosome for degradation and recycling. Autophagy is suggested to be critical for cell autonomous defense because many bacterial pathogens are detected within double-membrane vesicles upon internalization. Therefore, it is possible that drugs that target autophagy will be useful in a wide range of diseases downstream of bacterial infections. However, in addition to a direct microbicidal mechanism, autophagy has many substrates and cell type-specific functions that may contribute to the outcome of an infection. Thus, we chose to re-examine the role of autophagy in vivo using two model pathogens ? Salmonella enterica Typhimurium and Staphylococcus aureus. We chose to investigate S. Typhimurium because previous in vitro studies extensively demonstrated that this bacterium is targeted for degradation through autophagy. In contrast, in vitro experiments indicate that S. aureus uses the autophagy machinery for intracellular survival. In preliminary data, we demonstrate that inhibiting autophagy in vivo leads to the opposite outcome that is predicted by the literature. Specifically, autophagy mutants were protected from S. Typhimurium and susceptible to S. aureus. The goal of this proposal is to elucidate the physiological mechanism by which autophagy functions during infection by these two important bacterial pathogens.
In Aim 1, we will test a model in which S. Typhimurium recruits the autophagy machinery to repair the Salmonella-containing vacuole (SCV) and evade innate immune sensors.
In Aim 2, we will define a novel role for autophagy in regulating the cell surface proteome of the host cells, a function that is critical in limiting damage caused by a pore-forming toxin produced by S. aureus. The results from the proposed experiments will challenge the existing paradigm on the role of autophagy in antimicrobial defense and guide the proper use of drugs that target autophagy.

Public Health Relevance

The process of autophagy is a major way in which cells defend themselves against damage. In this proposal, we will investigate the role of autophagy in defense against two disease-causing bacteria that are known for their ability to damage cells, Salmonella enterica Typhimurium and Staphylococcus aureus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI121244-01A1
Application #
9237684
Study Section
Immunity and Host Defense (IHD)
Program Officer
Alexander, William A
Project Start
2016-11-10
Project End
2021-10-31
Budget Start
2016-11-10
Budget End
2017-10-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010
Martin, Patricia K; Marchiando, Amanda; Xu, Ruliang et al. (2018) Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota. Nat Microbiol 3:1131-1141
Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822
Neil, Jessica A; Cadwell, Ken (2018) The Intestinal Virome and Immunity. J Immunol 201:1615-1624
Wong, Serre-Yu; Cadwell, Ken (2018) There was collusion: Microbes in inflammatory bowel disease. PLoS Pathog 14:e1007215
Wong, Serre-Yu; Coffre, Maryaline; Ramanan, Deepshika et al. (2018) B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains. J Immunol 201:1442-1451
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
Blake, Kimbria J; Baral, Pankaj; Voisin, Tiphaine et al. (2018) Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun 9:37
Lubkin, Ashira; Torres, Victor J (2017) Bacteria and endothelial cells: a toxic relationship. Curr Opin Microbiol 35:58-63
Matsuzawa-Ishimoto, Yu; Shono, Yusuke; Gomez, Luis E et al. (2017) Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J Exp Med 214:3687-3705
Cadwell, Ken (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16:661-675