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

Parkinson, Edward ORCID: https://orcid.org/0009-0006-4552-9495, Watkins, William ORCID: https://orcid.org/0000-0003-3262-6588, Edkins, Sarah ORCID: https://orcid.org/0000-0003-0717-1972, McLaren, James ORCID: https://orcid.org/0000-0002-7021-5934, Clements, Michelle N., Andrews, Robert, Liberatore, Federico ORCID: https://orcid.org/0000-0001-9900-5108, Lutsar, Irja, Turner, Mark A., Roilides, Emmanuel, Heath, Paul T., Sharland, Michael, Hill, Louise F., Ghazal, Peter ORCID: https://orcid.org/0000-0003-0035-2228, Huertas, Tatiana Munera, Khan, Uzma, Ilmoja, Mari-Liis, Hallik, Maarja, Metsvaht, Tuuli, Kalamees, Riste, Karachristou, Korina, Vontzalidis, Adamantios, Anatolitou, Fani, Petropoulou, Chryssoula, Siahanidou, Tania, Nikaina, Eirini, Papaevangelou, Vassiliki, Triantafyllidou, Pinelopi, Sarafidis, Kosmas, Kontou, Angeliki, Nika, Angeliki, Tataropoulou, Kassandra, Mitsiakos, George, Iosifidis, Elias, Gialamprinou, Dimitra, Martinelli, Stefano, Ilardi, Laura, Baraldi, Eugenio, Bonadies, Luca, Del Vecchio, Antonio, Franco, Caterina, Dotta, Andrea, De Luca, Maia, Tzialla, Chryssoula, Alonso-Diaz, Clara, de Alba Romero, Concepción, de la Cruz, Javier, Catalina Morales-Betancourt, Paola, Alarcon Allen, Ana, Reyné, Mar, Mahaveer, Ajit, Booth, Nicola, Bilardi, Davide, Donà, Daniele, Rawcliffe, Louise, Bafadal, Basma, Roberts, Deborah, Silvestri, Antonella, Manfredi, Cristina, Felisi, Mariagrazia and Gandini, Paola 2025. A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis. Science Translational Medicine 17 (826) , eadt1938. 10.1126/scitranslmed.adt1938

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Computer Science & Informatics Schools > Medicine
Additional Information:	RRS applied 27/11/2025 AB
Publisher:	American Association for the Advancement of Science
ISSN:	1946-6234
Date of First Compliant Deposit:	27 November 2025
Date of Acceptance:	17 October 2025
Last Modified:	27 Nov 2025 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/182719

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