Enteric pathogens, which represent a major group of disease-causing agents, must overcome barrier immunity within the intestinal environment to infect a host. To counter this, the gastrointestinal tract has evolved as a physical and immunological barrier. Moreover, many enteric viruses infect intestinal epithelial cells which are both targets of and act as sentinels for infection. Increasing evidence suggests that epithelial cells sense infection directly to induce antimicrobial pathways. It is also clear that the microfloa within the intestinal tract plays a fundamental role in immunity and that imbalanced bacterial communities have detrimental consequences to immune defense. Aging animals present with immune deficiencies and an altered microbiome. Mechanistically, which microbes or microbial ligands, mediate these effects and how they impact antiviral immunity is unclear. To overcome our gap in knowledge of the molecular mechanisms that control enteric viral infection, we developed an oral model of arboviral infection using the powerful genetic model organism, Drosophila melanogaster. We found that the gut presents a high barrier to infection: young wild type flies are refractory to oral challenge with enteric viruses, while inoculation into the body cavity, which bypasses the gut, results in robust infection. Importantly, we found that the ERK pathway is activated in the intestinal epithelium by infection, and that genetic depletion of the ERK pathway only in the intestinal epithelium leads to increased infection. Furthermore, we found that the microbiota plays an important role in susceptibility to infection. In young flies, te loss of commensals in the gut led to increased permissivity to viral infection, suggesting that signals from the microbiota impact innate signaling. However, we found that older flies that present with dysbiosis are more susceptible to oral viral infection. Under these conditions ablation of the commensals protects the animals from enteric viral infection. Therefore, the microbiota, depending on its composition, can either be protective or detrimental for antiviral defenses. In this proposal we will address fundamental questions in antiviral immunity by determining the mechanisms by which the microbiota and epithelial cells control immunity in the intestine against human viruses, using a genetically tractable organism with a highly manipulable microbiome and short lifespan.

Public Health Relevance

Enteric viral pathogens are widespread and the leading cause of foodborne disease and thus understanding the mechanisms by which the gastrointestinal tract successfully restricts diverse enteric viruses is critical for the design of new intervention. While the intestinal environment is clearly restrictive to viral infection from insects to humans, few molecular mechanisms are known. Given the complexity of the gastrointestinal tract, including diverse microbiota, there is a need for simple model systems to decipher the molecular mechanisms that impact susceptibility to viral infection in the gut and lead to new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI122749-03
Application #
9378090
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Rothermel, Annette L
Project Start
2015-11-12
Project End
2020-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hughes, Elizabeth R; Winter, Maria G; Duerkop, Breck A et al. (2017) Microbial Respiration and Formate Oxidation as Metabolic Signatures of Inflammation-Associated Dysbiosis. Cell Host Microbe 21:208-219
Rausch, Keiko; Hackett, Brent A; Weinbren, Nathan L et al. (2017) Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus. Cell Rep 18:804-815
Sansone, Christine L; Cohen, Jonathan; Yasunaga, Ari et al. (2015) Microbiota-Dependent Priming of Antiviral Intestinal Immunity in Drosophila. Cell Host Microbe 18:571-81