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.
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. flexneri2457T-specific bacteriophage was isolated and assessed through kill curve experiments and infection assays with colorectal adenocarcinomaHT-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. flexneri2457T, 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. flexneri2457T 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.
Authors: Christina S Faherty; Christina Faherty; Jill M Harper; Terez Shea-Donohue; Eileen M Barry; James B Kaper; Alessio Fasano; James P Nataro Journal: PLoS One Date: 2012-11-16 Impact factor: 3.240
Authors: Florian Marks; Vera von Kalckreuth; Peter Aaby; Yaw Adu-Sarkodie; Muna Ahmed El Tayeb; Mohammad Ali; Abraham Aseffa; Stephen Baker; Holly M Biggs; Morten Bjerregaard-Andersen; Robert F Breiman; James I Campbell; Leonard Cosmas; John A Crump; Ligia Maria Cruz Espinoza; Jessica Fung Deerin; Denise Myriam Dekker; Barry S Fields; Nagla Gasmelseed; Julian T Hertz; Nguyen Van Minh Hoang; Justin Im; Anna Jaeger; Hyon Jin Jeon; Leon Parfait Kabore; Karen H Keddy; Frank Konings; Ralf Krumkamp; Benedikt Ley; Sandra Valborg Løfberg; Jürgen May; Christian G Meyer; Eric D Mintz; Joel M Montgomery; Aissatou Ahmet Niang; Chelsea Nichols; Beatrice Olack; Gi Deok Pak; Ursula Panzner; Jin Kyung Park; Se Eun Park; Henintsoa Rabezanahary; Raphaël Rakotozandrindrainy; Tiana Mirana Raminosoa; Tsiriniaina Jean Luco Razafindrabe; Emmanuel Sampo; Heidi Schütt-Gerowitt; Amy Gassama Sow; Nimako Sarpong; Hye Jin Seo; Arvinda Sooka; Abdramane Bassiahi Soura; Adama Tall; Mekonnen Teferi; Kamala Thriemer; Michelle R Warren; Biruk Yeshitela; John D Clemens; Thomas F Wierzba Journal: Lancet Glob Health Date: 2017-03 Impact factor: 26.763
Authors: Rachael B Chanin; Kourtney P Nickerson; Alejandro Llanos-Chea; Jeticia R Sistrunk; David A Rasko; Deepak Kumar Vijaya Kumar; John de la Parra; Jared R Auclair; Jessica Ding; Kelvin Li; Snaha Krishna Dogiparthi; Benjamin J D Kusber; Christina S Faherty Journal: mSphere Date: 2019-11-13 Impact factor: 4.389
Authors: Viktoria Hentschel; Frank Arnold; Thomas Seufferlein; Ninel Azoitei; Alexander Kleger; Martin Müller Journal: Stem Cells Int Date: 2021-01-07 Impact factor: 5.443