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Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production

Clostridioides difficile (CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentation...

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Autores principales: Cersosimo, Laura M., Graham, Madeline, Monestier, Auriane, Pavao, Aidan, Worley, Jay N., Peltier, Johann, Dupuy, Bruno, Bry, Lynn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245720/
https://www.ncbi.nlm.nih.gov/pubmed/37292778
http://dx.doi.org/10.1101/2023.05.19.541423
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author Cersosimo, Laura M.
Graham, Madeline
Monestier, Auriane
Pavao, Aidan
Worley, Jay N.
Peltier, Johann
Dupuy, Bruno
Bry, Lynn
author_facet Cersosimo, Laura M.
Graham, Madeline
Monestier, Auriane
Pavao, Aidan
Worley, Jay N.
Peltier, Johann
Dupuy, Bruno
Bry, Lynn
author_sort Cersosimo, Laura M.
collection PubMed
description Clostridioides difficile (CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentations of amino acids, with proline being a preferred reductive substrate. To investigate the in vivo effects of reductive proline metabolism on C. difficile’s virulence in an enriched gut nutrient environment, we evaluated wild-type and isogenic ΔprdB strains of ATCC43255 on pathogen behaviors and host outcomes in highly susceptible gnotobiotic mice. Mice infected with the ΔprdB mutant demonstrated extended survival via delayed colonization, growth and toxin production but ultimately succumbed to disease. In vivo transcriptomic analyses demonstrated how the absence of proline reductase activity more broadly disrupted the pathogen’s metabolism including failure to recruit oxidative Stickland pathways, ornithine transformations to alanine, and additional pathways generating growth-promoting substrates, contributing to delayed growth, sporulation, and toxin production. Our findings illustrate the central role for proline reductase metabolism to support early stages of C. difficile colonization and subsequent impact on the pathogen’s ability to rapidly expand and cause disease.
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spelling pubmed-102457202023-06-08 Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production Cersosimo, Laura M. Graham, Madeline Monestier, Auriane Pavao, Aidan Worley, Jay N. Peltier, Johann Dupuy, Bruno Bry, Lynn bioRxiv Article Clostridioides difficile (CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentations of amino acids, with proline being a preferred reductive substrate. To investigate the in vivo effects of reductive proline metabolism on C. difficile’s virulence in an enriched gut nutrient environment, we evaluated wild-type and isogenic ΔprdB strains of ATCC43255 on pathogen behaviors and host outcomes in highly susceptible gnotobiotic mice. Mice infected with the ΔprdB mutant demonstrated extended survival via delayed colonization, growth and toxin production but ultimately succumbed to disease. In vivo transcriptomic analyses demonstrated how the absence of proline reductase activity more broadly disrupted the pathogen’s metabolism including failure to recruit oxidative Stickland pathways, ornithine transformations to alanine, and additional pathways generating growth-promoting substrates, contributing to delayed growth, sporulation, and toxin production. Our findings illustrate the central role for proline reductase metabolism to support early stages of C. difficile colonization and subsequent impact on the pathogen’s ability to rapidly expand and cause disease. Cold Spring Harbor Laboratory 2023-08-28 /pmc/articles/PMC10245720/ /pubmed/37292778 http://dx.doi.org/10.1101/2023.05.19.541423 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Cersosimo, Laura M.
Graham, Madeline
Monestier, Auriane
Pavao, Aidan
Worley, Jay N.
Peltier, Johann
Dupuy, Bruno
Bry, Lynn
Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title_full Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title_fullStr Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title_full_unstemmed Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title_short Central in vivo mechanisms by which C. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
title_sort central in vivo mechanisms by which c. difficile’s proline reductase drives efficient metabolism, growth, and toxin production
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245720/
https://www.ncbi.nlm.nih.gov/pubmed/37292778
http://dx.doi.org/10.1101/2023.05.19.541423
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