Journal
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
Volume 68, Issue 4, Pages 509-516Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPG.0000000000002203
Keywords
bacteriophage; enteric pathogens; human intestinal organoid derived epithelial infection model; Shigella flexneri
Funding
- Bill and Melinda Gates Foundation [OPP1139856]
- National Institute of Allergy and Infectious Diseases [U19-AI082655, K22AI104755]
- National Science Foundation [MCB-1350625, 1521925]
- National Institutes of Health [5-P50-GM098792-05, 4-R33-AI121669-03, 1S10RR023594S10]
- Office of Naval Research [N00014-13-l-0424]
- Army Research Office [W911NF-ll-1-0281]
- Broad Institute
- Koch Institute
- Defense Threat Reduction Agency [HDTRAl-14-1-0007]
- Kenneth Rainin Foundation [2016-3066]
- Ellison Foundation [AG-NS-0948-12]
- Wertheimer Fund
- Institute for Soldier Nanotechnologies [W9111NF-13-D-0001]
- J-WAFS
- Novartis [14081955]
- Desphande Center at MIT
- Singapore-MIT Alliance for Research and Technology
- Center for Microbiome Informatics and Technology [15127713]
- Excet, Inc [17033835]
- National Institute of Neurological Disorders and Stroke [P30NS045776]
- Dake Family Foundation
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI082655, R33AI121669] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM098792] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P30NS045776] Funding Source: NIH RePORTER
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Objective: Enteric bacterial pathogens cause diarrheal disease and mortality at significant rates throughout the world, particularly in children younger than 5 years. Our ability to combat bacterial pathogens has been hindered by antibiotic resistance, a lack of effective vaccines, and accurate models of infection. With the renewed interest in bacteriophage therapy, we sought to use a novel human intestinal model to investigate the efficacy of a newly isolated bacteriophage against Shigella flexneri. Methods: An S. flexneri 2457T-specific bacteriophage was isolated and assessed through kill curve experiments and infection assays with colorectal adenocarcinoma HT-29 cells and a novel human intestinal organoid-derived epithelial monolayer model. In our treatment protocol, organoids were generated from intestinal crypt stem cells, expanded in culture, and seeded onto transwells to establish 2-dimensional monolayers that differentiate into intestinal cells. Results: The isolated bacteriophage efficiently killed S. flexneri 2457T, other S. flexneri strains, and a strain of 2457T harboring an antibiotic resistance cassette. Analyses with laboratory and commensal Escherichia coli strains demonstrated that the bacteriophage was specific to S. flexneri, as observed under co-culture conditions. Importantly, the bacteriophage prevented both S. flexneri 2457T epithelial cell adherence and invasion in both infection models. Conclusions: Bacteriophages offer feasible alternatives to antibiotics for eliminating enteric pathogens, confirmed here by the bacteriophage-targeted killing of S. flexneri. Furthermore, application of the organoid model has provided important insight into Shigella pathogenesis and bacteriophage-dependent intervention strategies. The screening platform described herein provides proof-of-concept analysis for the development of novel bacteriophage therapies to target antibiotic-resistant pathogens.
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