Sebastian J. Theobald, K. Dahm, Dinah Lange, Jannis Bastian Spintge, Sandra Winter, Angela Klingmüller, Lisa Holsten, Alexander Simonis, Elena De Domenico, Henning Walczak, Martina van Uelft, Joachim L. Schultze, Marc Beyer, Thomas Ulas, Isabelle Suárez, Jan Rybniker
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.