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Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of Vibrio cholerae during Coinfection with Enterotoxigenic Escherichia coli

Abdel-Haleem, Alyaa M. (författare)
King Abdullah University of Science and Technology (KAUST)
Ravikumar, Vaishnavi (författare)
Danmarks Tekniske Universitet,Technical University of Denmark,Novo Nordisk Fonden,Novo Nordisk Foundation
Ji, Boyang, 1983 (författare)
Chalmers tekniska högskola,Chalmers University of Technology
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Mineta, Katsuhiko (författare)
King Abdullah University of Science and Technology (KAUST)
Gao, Xin (författare)
King Abdullah University of Science and Technology (KAUST)
Nielsen, Jens B, 1962 (författare)
Chalmers tekniska högskola,Chalmers University of Technology,Novo Nordisk Fonden,Novo Nordisk Foundation
Gojobori, Takashi (författare)
King Abdullah University of Science and Technology (KAUST)
Mijakovic, Ivan, 1975 (författare)
Chalmers tekniska högskola,Chalmers University of Technology,Novo Nordisk Fonden,Novo Nordisk Foundation
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 (creator_code:org_t)
2020
2020
Engelska.
Ingår i: mSystems. - 2379-5077. ; 5:5
Relaterad länk:
https://research.cha... (primary) (free)
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https://doi.org/10.1...
https://research.cha...
https://research.cha...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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 co-culture 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Infectious Medicine (hsv//eng)
NATURVETENSKAP  -- Biologi -- Mikrobiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Microbiology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Nyckelord

diarrhea
genome-scale modeling
genome-scale reconstruction
drug target
coinfection
infectious diseases
constraint-based model
Vibrio cholera
flux balance analysis
cholera
computational modeling

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