Abstract
Background
One third of patients with Escherichia coli bacteraemia develop a dysregulated inflammatory response (sepsis/septic shock). Our objective was to investigate whether specific microbiological determinants of E. coli are associated to presentation with sepsis/shock.
Methods
A matched case-control study was performed; 101 case-patients with E. coli bacteraemia presenting with sepsis (SEPSIS-3 criteria) and 101 control-patients with E. coli bacteraemia without sepsis were matched by service, sex, age, Charlson index, acquisition and source of the bacteraemia and empirical treatment. Whole genome sequencing of E. coli isolates was performed (Illumina MiSeq Inc.). Sequence type, serotype, fimH type, virulence factors, antibiotic resistance genes, plasmid replicons pathogenicity islands and prophages were determined. A multivariate model was built for presentation with sepsis/septic shock using conditional logistic regression. The predictive capacity on the observed data was measured with the area under the ROC curve (AUROC) with 95% confidence intervals (CI).
Results
Here we show that in the multivariate model (adjusted OR; 95% CI), the ST69 clone (7.53; 1.06-35.05) and pic gene (4.38; 1.53-12.54) are associated to presentation with sepsis/shock, while the genes papC (0.30; 0.12-0.74) and fdeC (0.18; 0.03-1.32) show a protective effect. The AUROC of this model is 0.81 (95% CI 0.74-0.87).
Conclusions
We identify E. coli bacterial factors associated with severe clinical presentation in patients with bacteraemia. Further studies would be needed to consider these factors as potential preventive or therapeutic targets.
Plain language summary
Escherichia coli is the most common cause of invasive infections, including bacteraemia that often progresses to severe conditions like sepsis or septic shock. While many host factors determine the severity of illness, this study looked at the bacterial factors that may contribute to sepsis severity. We directly compared E. coli-infected patients with similar traits but either with or without sepsis to control for patient factors Our analysis revealed that the ST69 clone and the presence of the pic gene were significantly associated with an increased risk of sepsis/septic shock, whereas the adhesion genes papC and fdeC were associated with a lower risk. These key findings underscore a role for specific E. coli genetic factors in determining clinical severity, thereby providing potential bacterial targets for the development of improved diagnostics and novel preventive or therapeutic interventions.
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Data availability
Source data for Figs. 1, 2 and 3 are accessible from Supplementary Data 1, 2 and 3, respectively. The complete genome sequence data are publicly available in the European Nucleotide Archive (ENA) under Bioproject PRJEB62601. Researchers may gain access to an anonymised and de-identified version of the dataset presented in this article. To obtain access, a proposed use must first be approved by an independent review committee and the requestor must sign a data access agreement with the senior authors’ institution. Please submit all inquiries and proposals to jesusrb@us.es
Code availability
The custom source code to generate the study’s main results is publicly available at https://data.mendeley.com/datasets/4j8tw9wnwb/1. This material is provided under the licence CC BY NC 3.0, meaning you are free to adapt, copy or redistribute the material, providing you attribute appropriately and do not use the material for commercial purposes. Quality analysis of genome assemblies, genome annotation and pan-genome analysis were performed in QUAST v5.2.0, Bakta v1.6.1 and Roary v3.13.0, respectively. Phylogenomic tree reconstruction based on the best-scoring maximum-likelihood (ML) inference tree for a DNA alignment was performed in RAxML v8.2.12 and best-scoring ML inference tree with branch lengths corrected to account for recombination events in ClonalFrameML v1.12. Other bioinformatics analyses, including Principal Coordinate Analysis (PCoA), clustering based on PCoA, Boruta algorithm and Random Forest Models were performed in R v4.3.1 using the following core packages: tidyverse (2.0.0), caret (6.0-94), Boruta (8.0.0), ranger (0.17.0), vegan (2.6-4) and pROC (1.18.5).
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Acknowledgements
This study was funded by the Instituto de Salud Carlos III through grant PI16/01432 and co-funded by the European Union (Development Regional Fund ‘A Way to Achieve Europe’). The funders had no role in the design, collection of data, analysis and writing of the manuscript or the decision to publish. We would like to thank all local clinical and microbiological researchers at participating hospitals, members of the PROBAC REIPI/GEIRAS-SEIMC/SAMICEI Group, who helped recruit patients and collect the data.
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N.M., I.L.-H., J.R.-B. and A.P. were responsible for conceptualisation, formulating the overall research questions, methodology, formal analysis and writing of the original draft. N.M., I.L.-H., A.G.-M. and M.A.-R. were responsible for bioinformatics analysis. L.E.L.-C., P.M.M.-P.C., A.S.-D., A.J.-S., J.G., A.P.-N., L.B.-M., A.A., L.B.-P., A.d.-J., A.S.-A., J.M.S.-C., C.N.-K., J.M.R.-I., C.A.-C., F.G.-S., A.B., I.G.-L., C.C.-A., I.P.-C., T.M.-C., B.B.-C. participated by reviewing the design, recruiting patients and isolates and thoroughly reviewed the manuscript. J.K.-V. and P.N. participated reviewing the design, performing analysis and reviewed the manuscript. All authors have seen and approved the submitted version of this manuscript and accept responsibility for the decision to submit for publication. I.L.-H., J.R.-B. and A.P. were responsible for funding acquisition, project administration, supervision and coordinating the study.
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L.E.L.-C. reports consulting fees from Angelini Pharm and payments for presentations from Correvio Pharma Corp., Gilead Sciences, Inc. and ViiV Healthcare. L.B.-P. reports payments for presentations in educational events from Tillotts Pharma AG and Menarini Group and support for attending meetings and/or travel from Pfizer, Inc. All other authors declare no competing interests.
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Communications Medicine thanks Evdoxia Kyriazopoulou, Valentino D’Onofrio and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Maldonado, N., López-Hernández, I., Valik, J.K. et al. A matched case-control study on Escherichia coli factors contributing to sepsis and septic shock in bacteraemic patients. Commun Med (2026). https://doi.org/10.1038/s43856-025-01364-x
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DOI: https://doi.org/10.1038/s43856-025-01364-x
