A multicenter spatial transcriptomics atlas of human tuberculosis and non-tuberculous mycobacterial disease

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary Granulomas are the hallmark of mycobacterial (MB) infections, forming structured immune environments that contain bacteria but also drive disease persistence. However, their spatial and functional organization remains unclear. Using spatial RNA sequencing on 38 patient samples, we identified five distinct granuloma niches: a necrotic core, an immune-activated inner niche, an inflammatory and an extracellular matrix (ECM)-remodeling middle niche, an outer structural niche, and a tertiary lymphoid structure niche supporting antigen presentation. Immune activity peaks in the inner niche, transitioning to fibrosis at the periphery. Lymph node granulomas display reduced fibroblast involvement but stronger JAK-STAT activation. Mycobacterium tuberculosis (MTB) granulomas exhibit heightened JAK-STAT and IFN-γ signaling, while non-tuberculous mycobacteria (NTM) granulomas show increased hypoxia signatures. Compared to sarcoidosis, MB granulomas feature a structured adaptive immune response, marked by the clustering of plasma cells. Our findings, accessible via https://lab-li.ciim-hannover.de/mb-granuloma/ , define key disease signatures, guiding biomarker discovery and therapeutic targeting in granuloma-related diseases.

Authors 20

1. Xun Jiang corresponding

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

2. Leonard Christian

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

3. Liang Zhou

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

4. Xiaoyi Zheng

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

5. Nienke van Unen

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

6. Lavinia Neubert

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

7. Jan C. Kamp

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

8. Moritz Z. Kayser

   Medizinische Hochschule Hannover

   Affiliation as printed

   Hannover Medical School;

9. Jens Michael Hohlfeld

   Fraunhofer Institute for Toxicology and Experimental Medicine

   Affiliation as printed

   Fraunhofer ITEM;

10. Hortense Slevogt

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

11. Marius M. Hoeper

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

12. Naftali Kaminski

    Yale University

    Affiliation as printed

    Yale School of Medicine;

13. Tobias Welte

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

14. Jan Fuge

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

15. Felix C. Ringshausen

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

16. Robert Homer

    Yale University

    Affiliation as printed

    Yale School of Medicine;

17. Danny David Jonigk Aachen Aachen Medical School

    RWTH Aachen University

    Affiliation as printed

    Aachen Medical School;

18. Cheng‐Jian Xu

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

19. Jonas C. Schupp

    Medizinische Hochschule Hannover

    Affiliation as printed

    Hannover Medical School;

20. Yang Li

    Helmholtz Centre for Infection Research

    Affiliation as printed

    Helmholtz center for infection research