Identification of a spatially organized TREM2-associated permissive macrophage niche in human pulmonary tuberculosis alveolar pneumonia
Abstract Pulmonary tuberculosis (TB), caused by lung infection with Mycobacterium tuberculosis ( Mtb ), often manifests both alveolar pneumonia and aggregation of immune cells containing Mtb , termed granulomas, within the same lung. Here, we integrate spatial transcriptomics, single-cell RNA sequencing, high-resolution imaging, and functional assays of lung biopsies from four men with pulmonary TB to compare alveolar pneumonia with adjacent granulomas. We find that alveolar TB pneumonia is enriched for TREM2⁺ lipid-laden macrophages characterized by increased lipid metabolism gene expression, reduced T cell infiltration, attenuated antimicrobial gene expression, and abundant Mtb transcripts and antigens. By contrast, neighboring granulomas exhibit organized lymphoid architecture and robust antimicrobial programs. In vitro, Mtb lipids induce TREM2 expression, activate TREM2–DAP12 signaling, and promote lipid droplet accumulation in primary human monocyte-derived macrophages (MDM). Furthermore, TREM2 + MDMs are more susceptible to in vitro Mtb infection. When treating MDMs with 1,25-dihydroxyvitamin D₃, which induces antimicrobial macrophage programs, TREM2 + MDM numbers, lipid droplet abundance and Mtb viability are decreased. Thus, we propose a spatially localized, alveolar pneumonia-intrinsic TREM2⁺ macrophage program that potentially contributes to Mtb persistence in pulmonary TB infection in humans.
Authors
- Feiyang Ma (ORCID: https://orcid.org/0000-0002-6260-0787)
- Bruno Silva Andrade (ORCID: https://orcid.org/0000-0002-8031-9454)
- Matteo Pellegrini (ORCID: https://orcid.org/0000-0001-9355-9564)
- Eynav Klechevsky (ORCID: https://orcid.org/0000-0001-6121-1571)
- Mohamed‐Ridha Barbouche (ORCID: https://orcid.org/0009-0009-4145-8644)
- Cenfu Wei (ORCID: https://orcid.org/0000-0003-3368-4974)
- Chaouki Benabdessalem (ORCID: https://orcid.org/0000-0001-7309-6814)
- Parambir S. Dulai (ORCID: https://orcid.org/0000-0002-9514-2321)
- Threnesan Naidoo (ORCID: https://orcid.org/0000-0002-1864-4301)
- Samuel W. French (ORCID: https://orcid.org/0000-0002-7611-881X)
- Robert L. Modlin (ORCID: https://orcid.org/0000-0003-4720-031X)
- Daniel L. Barber (ORCID: https://orcid.org/0000-0001-7008-7509)
- Marco Colonna (ORCID: https://orcid.org/0000-0001-5222-4987)
- Emna Romdhane (ORCID: https://orcid.org/0000-0003-0748-8195)
- Bryan D. Bryson (ORCID: https://orcid.org/0000-0003-1716-6712)
- Steven J. Bensinger (ORCID: https://orcid.org/0000-0002-9657-4206)
- Soumaya Rammeh (ORCID: https://orcid.org/0000-0003-0366-4630)
- Adrie J. C. Steyn (ORCID: https://orcid.org/0000-0001-9177-8827)
- Jonathan Perrie
- Julie West
- Rosane M. B. Teles (ORCID: https://orcid.org/0000-0003-2908-3244)
- Yiqian Gu (ORCID: https://orcid.org/0009-0000-9131-6278)
- Madeline Brown
- Karen Lam (ORCID: https://orcid.org/0000-0003-4635-7008)
- Lilah A. Mansky
- Kimia Rategh
- Kapongo Lumamba
- Priscila R. Andrade
- Linda Fischbacher
- Prajan Divaka
- John T. Belisle
- Barry R. Bloom
- Aparna Pillai
Institutions
- Tunis University (TN)
- Northwestern University (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- Bruker (United States) (US)
- Washington University in St. Louis (US)
- University of Alabama at Birmingham (US)
- Africa Health Research Institute (ZA)
- National Institute of Allergy and Infectious Diseases (US)
- Institut Pasteur de Tunis (TN)
- Tunis El Manar University (TN)
- Massachusetts Institute of Technology (US)
- Colorado State University (US)
- Walter Sisulu University (ZA)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-21
- DOI
- https://doi.org/10.1038/s41467-026-76814-8
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- University of California, Los Angeles
- Jonsson Comprehensive Cancer Center
- California NanoSystems Institute