Accumulating evidence support the role of bacterial members of the gut microbiota in host defense and a variety of immune disorders, such as inflammatory bowel disease (IBD). The mammalian gastrointestinal tract also harbors diverse animal viruses. Despite their ubiquitous presence, the functional and mechanistic consequences of intestinal colonization by viruses beyond their role as diarrheal pathogens has been unclear. Over the previous funding periods of this award, we developed the murine norovirus (MNV) model as a tractable experimental system to address this major gap in our knowledge. We found that MNV can function as a symbiotic virus by providing benefits to the host, such as protection against secondary bacterial infection. At the same time, MNV induces intestinal abnormalities in mice with a mutation in Atg16L1, an IBD susceptibility gene that participates in the cellular degradative pathway of autophagy. The main objective of this proposal is to use the MNV model to define the mechanisms that determine whether intestinal colonization by a viral symbiont leads to beneficial or adverse outcomes for the host. We introduce data showing that MNV infection can significantly improve survival of newly weaned mice from lethal infection by the Gram-negative bacterial pathogen Citrobacter rodentium. We propose to use this model to elucidate how RNA sensing pathways are induced by a viral symbiont to mediate cross-protection during early-life infection by an enteric bacterial pathogen, a leading cause of mortality. In parallel, we will investigate how Atg16L1 mutation makes an otherwise beneficial virus become harmful. Our preliminary data suggests a novel mechanism in which MNV infection replaces anti-inflammatory lymphocytes in the gut with cytotoxic subsets that induce necrotic death of Paneth cells, a key secretory epithelial cell implicated in human IBD. Defining the mechanistic details of these processes will yield new insight into the nature of a viral symbiont in the gut, and may reveal new pathways involved in the resolution of tissue injury that are distinct from those previously examined during bacterial colonization.

Public Health Relevance

Although diverse animal viruses inhabit the intestines of healthy individuals and patients with chronic diseases, how they impact our physiology is unclear. We developed animal models in which a viral member of the gut microbiota defends against bacterial infections, but triggers inflammatory bowel disease in a genetically susceptible host. We will apply this model system towards uncovering the mechanisms that determine whether intestinal colonization by a virus leads to a beneficial or adverse outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK093668-10
Application #
10133411
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2011-09-20
Project End
2024-08-31
Budget Start
2020-09-19
Budget End
2021-08-31
Support Year
10
Fiscal Year
2020
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
10016
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
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
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
Alissafi, Themis; Banos, Aggelos; Boon, Louis et al. (2017) Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. J Clin Invest 127:2789-2804
Cadwell, Ken (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16:661-675
Ramanan, Deepshika; Bowcutt, Rowann; Lee, Soo Ching et al. (2016) Helminth infection promotes colonization resistance via type 2 immunity. Science 352:608-12

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