Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications

Kaori L. Fonseca, Juan José Lozano, Albert Despuig, Dominic Habgood-Coote, Julia Sidorova, Diego Aznar, Lilibeth Arias, Álvaro Del Río-Álvarez, Juan Carrillo-Reixach, Aaron Goff, Leticia Muraro Wildner, Shota Gogishvili, Keti Nikolaishvili, Natalia Shubladze, Zaza Avaliani, Gustavo Tapia, Paula Rodríguez-Martínez, Pere-Joan Cardona, Federico Martinón-Torres, Antonio Salas, Alberto Gómez-Carballa, Carolina Armengol, Simon J. Waddell, Myrsini Kaforou, Anne O’Garra, Sergo Vashakidze and Cristina Vilaplana ()
Additional contact information
Kaori L. Fonseca: Fundació Institut Germans Trias i Pujol (IGTP)
Juan José Lozano: Centro de Investigación Biomédica en Red de Enfermedades Hepática y Digestivas (CIBERehd)
Albert Despuig: Fundació Institut Germans Trias i Pujol (IGTP)
Dominic Habgood-Coote: Imperial College London
Julia Sidorova: Centro de Investigación Biomédica en Red de Enfermedades Hepática y Digestivas (CIBERehd)
Diego Aznar: Fundació Institut Germans Trias i Pujol (IGTP)
Lilibeth Arias: Fundació Institut Germans Trias i Pujol (IGTP)
Álvaro Del Río-Álvarez: Germans Trias i Pujol Research Institute (IGTP)
Juan Carrillo-Reixach: Germans Trias i Pujol Research Institute (IGTP)
Aaron Goff: University of Sussex
Leticia Muraro Wildner: University of Sussex
Shota Gogishvili: National Center for Tuberculosis and Lung Diseases (NCTLD)
Keti Nikolaishvili: National Center for Tuberculosis and Lung Diseases (NCTLD)
Natalia Shubladze: National Center for Tuberculosis and Lung Diseases (NCTLD)
Zaza Avaliani: National Center for Tuberculosis and Lung Diseases (NCTLD)
Gustavo Tapia: Hospital Germans Trias i Pujol
Paula Rodríguez-Martínez: Hospital Germans Trias i Pujol
Pere-Joan Cardona: Fundació Institut Germans Trias i Pujol (IGTP)
Federico Martinón-Torres: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
Antonio Salas: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
Alberto Gómez-Carballa: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
Carolina Armengol: Germans Trias i Pujol Research Institute (IGTP)
Simon J. Waddell: University of Sussex
Myrsini Kaforou: Imperial College London
Anne O’Garra: The Francis Crick Institute
Sergo Vashakidze: National Center for Tuberculosis and Lung Diseases (NCTLD)
Cristina Vilaplana: Fundació Institut Germans Trias i Pujol (IGTP)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The tuberculosis (TB) lesion is a complex structure, contributing to the overall spectrum of TB. We characterise, using RNA sequencing, 44 fresh human pulmonary TB lesion samples from 13 TB individuals (drug-sensitive and multidrug-resistant TB) undergoing therapeutic surgery. We confirm clear separation between the TB lesion and adjacent non-lesional tissue, with the lesion samples consistently displaying increased inflammatory profile despite heterogeneity. Using weighted correlation network analysis, we identify 17 transcriptional modules associated with TB lesion and demonstrate a gradient of immune-related transcript abundance according to spatial organization of the lesion. Furthermore, we associate the modular transcriptional signature of the TB lesion with clinical surrogates of treatment efficacy and TB severity. We show that patients with worse disease present an overabundance of immune/inflammation-related modules and downregulated tissue repair and metabolism modules. Our findings provide evidence of a relationship between clinical parameters, treatment response and immune signatures at the infection site.

Date: 2025
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DOI: 10.1038/s41467-025-60255-w

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