Deep immune profiling delineates hallmarks of disease heterogeneity in extrapulmonary tuberculosis

Sebastian J. Theobald, Kilian Dahm, Dinah Lange, Jannis B. Spintge, Sandra Winter, Angela Klingmüller, Lisa Holsten, Alexander Simonis, Elena Domenico, Henning Walczak, Martina Uelft, Joachim L. Schultze, Marc D. Beyer, Thomas Ulas (), Isabelle Suárez and Jan Rybniker ()
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Sebastian J. Theobald: University of Cologne
Kilian Dahm: German Center for Neurodegenerative Diseases (DZNE)
Dinah Lange: University of Cologne
Jannis B. Spintge: German Center for Neurodegenerative Diseases (DZNE)
Sandra Winter: University of Cologne
Angela Klingmüller: University of Cologne
Lisa Holsten: German Center for Neurodegenerative Diseases (DZNE)
Alexander Simonis: University of Cologne
Elena Domenico: German Center for Neurodegenerative Diseases (DZNE)
Henning Walczak: University College London
Martina Uelft: German Center for Neurodegenerative Diseases (DZNE)
Joachim L. Schultze: German Center for Neurodegenerative Diseases (DZNE)
Marc D. Beyer: German Center for Neurodegenerative Diseases (DZNE)
Thomas Ulas: German Center for Neurodegenerative Diseases (DZNE)
Isabelle Suárez: University of Cologne
Jan Rybniker: University of Cologne

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Our understanding of the immune response in tuberculosis (TB) remains incomplete. This applies in particular to extrapulmonary TB (EPTB), a highly heterogeneous disease affecting up to 30% of patients in certain regions. Based on data-driven clustering of blood transcriptomes in an EPTB patient cohort, we define three highly distinct immunotypes. Combining bulk with single-cell RNA-sequencing delineates immunological trajectories characterized by dynamic IFN- and IL-1-mediated signalling in monocytes, alongside hyperactivation of T and NK cells, ultimately resulting in extensive immune dysregulation. Integrative analysis of multi-omics data provides deep insights into different layers of the anti-tuberculous immune response and the identification of immunotypes enabling stratification strategies for personalized host-directed treatments. In addition, our comprehensive approach helps to develop an accurate diagnostic gene expression signature for both EPTB and pulmonary TB highlighting the translational potential of our data.

Date: 2025
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DOI: 10.1038/s41467-025-65561-x

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