A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis

Sepsis is a leading cause of mortality and morbidity in neonates yet remains difficult to diagnose. This leads to widespread empiric antibiotic therapy, which can facilitate the development of antimicrobial resistance. How the dysregulated host response to infection and sepsis evolves after antibiotic treatment is poorly understood. Temporal gene expression in neonates with microbiologically confirmed sepsis, treated with the antibiotic vancomycin as part of a randomized controlled trial, was profiled to reveal a treatment-responsive gene signature. The signature exhibited a rapid reversal of the septic state, observable within 24 hours of the initiation of therapy. Unexpectedly, response rates associated with the adaptive immune system were among the fastest, and these changes were reproduced in both pediatric and adult patients with sepsis, indicating conservation and reversibility of sepsis signatures across the life course. We demonstrated how these treatment-responsive genes could be translated into a prognostic clinical measure, exhibiting strong agreement with clinical assessments. Network modeling of sepsis-responsive genes identified a signature associated with treatment comprising an early transient elevation of antimicrobial defensive genes, suggesting an impaired bactericidal response in neonatal sepsis. These findings suggest that the host response is regulated in sepsis and offer insights into early prognostic approaches for reducing antibiotic overuse.

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Publication Details

Journal
Science Translational Medicine
Published
2025-11-26
DOI
https://doi.org/10.1126/scitranslmed.adt1938
Primary Topic
Neonatal and Maternal Infections
Type
article
Field-Weighted Citation Impact
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article

A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis

Sarah Edkins, Clara Alonso Díaz, Mariagrazia Felisi, Edward Parkinson et al.
Science Translational Medicine
Neonatal and Maternal Infections
article

A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis

Sarah Edkins, Clara Alonso Díaz, Mariagrazia Felisi, Edward Parkinson, Stefano Martinelli, Luca Bonadies, Εlias Iosifidis, Basma Bafadal, Mari‐Liis Ilmoja, Irja Lutsar, Louise Rawcliffe, Kosmas Sarafidis, Korina Karachristou, Dimitra Gialamprinou, Paul Trafford Heath, Chryssoula Petropoulou, Ana Alarcón, Daniele Donà, Chryssoula Tzialla, Ajit Mahaveer, Angeliki Kontou, Eirini Nikaina, Andrea Dotta, Caterina Franco, Angeliki Nika, L. Hill, Eugenio Baraldi, Emmanuel Roilides, Laura Ilardi, Maia De Luca, Javier de la Cruz, Uzma Khan, Mike Sharland, Concepción de Alba Romero, Vassiliki Papaevangelou, William J. Watkins, Davide Bilardi, Maarja Hallik, Tania Siahanidou, James E. McLaren, Peter Ghazal, Robert Andrews, Michelle Clements, Riste Kalamees, Federico Liberatore, Alberto Silvestri, Tatiana Munera Huertas, Georgıos Mitsiakos, Deborah Roberts, P. Gandini, Fani Anatolitou, Adamantios Vontzalidis, Pinelopi Triantafyllidou, Tuuli Metsvaht, Kassandra Tataropoulou, Paola Catalina Morales-Betancourt, M. Turner, Mar Reyné, Antonio Del Vecchio, Chiara Manfredi, Nicola Booth
article en

Abstract

Sepsis is a leading cause of mortality and morbidity in neonates yet remains difficult to diagnose. This leads to widespread empiric antibiotic therapy, which can facilitate the development of antimicrobial resistance. How the dysregulated host response to infection and sepsis evolves after antibiotic treatment is poorly understood. Temporal gene expression in neonates with microbiologically confirmed sepsis, treated with the antibiotic vancomycin as part of a randomized controlled trial, was profiled to reveal a treatment-responsive gene signature. The signature exhibited a rapid reversal of the septic state, observable within 24 hours of the initiation of therapy. Unexpectedly, response rates associated with the adaptive immune system were among the fastest, and these changes were reproduced in both pediatric and adult patients with sepsis, indicating conservation and reversibility of sepsis signatures across the life course. We demonstrated how these treatment-responsive genes could be translated into a prognostic clinical measure, exhibiting strong agreement with clinical assessments. Network modeling of sepsis-responsive genes identified a signature associated with treatment comprising an early transient elevation of antimicrobial defensive genes, suggesting an impaired bactericidal response in neonatal sepsis. These findings suggest that the host response is regulated in sepsis and offer insights into early prognostic approaches for reducing antibiotic overuse.

Science Translational MedicineVol. 17(826)
University of Liverpool (GB), St George's, University of London (GB), Aristotle University of Thessaloniki (GR), MRC Clinical Trials Unit at UCL (GB), Institute of Infection and Immunity (CA), University College London (GB), University of Tartu (EE), Cardiff University (GB)
Openalex Percentile: Top 53%
Neonatal and Maternal Infections
DOISourceOpenAlex
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