Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>

ABSTRACT Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models (GEMs) to explore the effect of coinfection of the diarrheagenic pathogen Vibrio choler...

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Autores principales:	Alyaa M. Abdel-Haleem, Vaishnavi Ravikumar, Boyang Ji, Katsuhiko Mineta, Xin Gao, Jens Nielsen, Takashi Gojobori, Ivan Mijakovic
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	infectious diseases cholera diarrhea coinfection drug target flux balance analysis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/be2ba7c1adef4e90868158e2f4212684
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spelling	oai:doaj.org-article:be2ba7c1adef4e90868158e2f42126842021-12-02T18:15:47ZIntegrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>10.1128/mSystems.00491-202379-5077https://doaj.org/article/be2ba7c1adef4e90868158e2f42126842020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00491-20https://doaj.org/toc/2379-5077ABSTRACT Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models (GEMs) to explore the effect of coinfection of the diarrheagenic pathogen Vibrio cholerae with another enteric pathogen, enterotoxigenic Escherichia coli (ETEC). Model predictions showed that V. cholerae metabolic capabilities were increased due to ample cross-feeding opportunities enabled by ETEC. This is in line with increased severity of cholera symptoms known to occur in patients with dual infections by the two pathogens. In vitro coculture systems confirmed that V. cholerae growth is enhanced in cocultures relative to single cultures. Further, expression levels of several V. cholerae metabolic genes were significantly perturbed as shown by dual RNA sequencing (RNAseq) analysis of its cocultures with different ETEC strains. A decrease in ETEC growth was also observed, probably mediated by nonmetabolic factors. Single gene essentiality analysis predicted conditionally independent genes that are essential for the pathogen’s growth in both single-infection and coinfection scenarios. Our results reveal growth differences that are of relevance to drug targeting and efficiency in polymicrobial infections. IMPORTANCE Most studies proposing new strategies to manage and treat infections have been largely focused on identifying druggable targets that can inhibit a pathogen's growth when it is the single cause of infection. In vivo, however, infections can be caused by multiple species. This is important to take into account when attempting to develop or use current antibacterials since their efficacy can change significantly between single infections and coinfections. In this study, we used genome-scale metabolic models (GEMs) to interrogate the growth capabilities of Vibrio cholerae in single infections and coinfections with enterotoxigenic E. coli (ETEC), which cooccur in a large fraction of diarrheagenic patients. Coinfection model predictions showed that V. cholerae growth capabilities are enhanced in the presence of ETEC relative to V. cholerae single infection, through cross-fed metabolites made available to V. cholerae by ETEC. In vitro, cocultures of the two enteric pathogens further confirmed model predictions showing an increased growth of V. cholerae in coculture relative to V. cholerae single cultures while ETEC growth was suppressed. Dual RNAseq analysis of the cocultures also confirmed that the transcriptome of V. cholerae was distinct during coinfection compared to single-infection scenarios where processes related to metabolism were significantly perturbed. Further, in silico gene-knockout simulations uncovered discrepancies in gene essentiality for V. cholerae growth between single infections and coinfections. Integrative model-guided analysis thus identified druggable targets that would be critical for V. cholerae growth in both single infections and coinfections; thus, designing inhibitors against those targets would provide a broader spectrum of coverage against cholera infections.Alyaa M. Abdel-HaleemVaishnavi RavikumarBoyang JiKatsuhiko MinetaXin GaoJens NielsenTakashi GojoboriIvan MijakovicAmerican Society for Microbiologyarticleinfectious diseasescholeradiarrheacoinfectiondrug targetflux balance analysisMicrobiologyQR1-502ENmSystems, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	infectious diseases cholera diarrhea coinfection drug target flux balance analysis Microbiology QR1-502
spellingShingle	infectious diseases cholera diarrhea coinfection drug target flux balance analysis Microbiology QR1-502 Alyaa M. Abdel-Haleem Vaishnavi Ravikumar Boyang Ji Katsuhiko Mineta Xin Gao Jens Nielsen Takashi Gojobori Ivan Mijakovic Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
description	ABSTRACT Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models (GEMs) to explore the effect of coinfection of the diarrheagenic pathogen Vibrio cholerae with another enteric pathogen, enterotoxigenic Escherichia coli (ETEC). Model predictions showed that V. cholerae metabolic capabilities were increased due to ample cross-feeding opportunities enabled by ETEC. This is in line with increased severity of cholera symptoms known to occur in patients with dual infections by the two pathogens. In vitro coculture systems confirmed that V. cholerae growth is enhanced in cocultures relative to single cultures. Further, expression levels of several V. cholerae metabolic genes were significantly perturbed as shown by dual RNA sequencing (RNAseq) analysis of its cocultures with different ETEC strains. A decrease in ETEC growth was also observed, probably mediated by nonmetabolic factors. Single gene essentiality analysis predicted conditionally independent genes that are essential for the pathogen’s growth in both single-infection and coinfection scenarios. Our results reveal growth differences that are of relevance to drug targeting and efficiency in polymicrobial infections. IMPORTANCE Most studies proposing new strategies to manage and treat infections have been largely focused on identifying druggable targets that can inhibit a pathogen's growth when it is the single cause of infection. In vivo, however, infections can be caused by multiple species. This is important to take into account when attempting to develop or use current antibacterials since their efficacy can change significantly between single infections and coinfections. In this study, we used genome-scale metabolic models (GEMs) to interrogate the growth capabilities of Vibrio cholerae in single infections and coinfections with enterotoxigenic E. coli (ETEC), which cooccur in a large fraction of diarrheagenic patients. Coinfection model predictions showed that V. cholerae growth capabilities are enhanced in the presence of ETEC relative to V. cholerae single infection, through cross-fed metabolites made available to V. cholerae by ETEC. In vitro, cocultures of the two enteric pathogens further confirmed model predictions showing an increased growth of V. cholerae in coculture relative to V. cholerae single cultures while ETEC growth was suppressed. Dual RNAseq analysis of the cocultures also confirmed that the transcriptome of V. cholerae was distinct during coinfection compared to single-infection scenarios where processes related to metabolism were significantly perturbed. Further, in silico gene-knockout simulations uncovered discrepancies in gene essentiality for V. cholerae growth between single infections and coinfections. Integrative model-guided analysis thus identified druggable targets that would be critical for V. cholerae growth in both single infections and coinfections; thus, designing inhibitors against those targets would provide a broader spectrum of coverage against cholera infections.
format	article
author	Alyaa M. Abdel-Haleem Vaishnavi Ravikumar Boyang Ji Katsuhiko Mineta Xin Gao Jens Nielsen Takashi Gojobori Ivan Mijakovic
author_facet	Alyaa M. Abdel-Haleem Vaishnavi Ravikumar Boyang Ji Katsuhiko Mineta Xin Gao Jens Nielsen Takashi Gojobori Ivan Mijakovic
author_sort	Alyaa M. Abdel-Haleem
title	Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_short	Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_full	Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_fullStr	Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_full_unstemmed	Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_sort	integrated metabolic modeling, culturing, and transcriptomics explain enhanced virulence of <named-content content-type="genus-species">vibrio cholerae</named-content> during coinfection with enterotoxigenic <named-content content-type="genus-species">escherichia coli</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/be2ba7c1adef4e90868158e2f4212684
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Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of <named-content content-type="genus-species">Vibrio cholerae</named-content> during Coinfection with Enterotoxigenic <named-content content-type="genus-species">Escherichia coli</named-content>

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