Peer-reviewedCC BYNature communications
Identification of a spatially organized TREM2-associated permissive macrophage niche in human pulmonary tuberculosis alveolar pneumonia.
20 affiliations
- 1Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- 2Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.
- 3Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, USA.
- 4Northwestern University, Chicago, IL, USA.
- 5Bruker Spatial Biology, Bothell, WA, USA.
- 6Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
- 7Africa Health Research Institute, Durban, South Africa.
- 8Department of Forensic and Legal Medicine, Walter Sisulu University, Mthatha, South Africa.
- 9Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- 10Department of Pathology, Charles Nicolle Hospital, Tunis, Tunisia; LR23ES02, Faculté de Médecine de Tunis, Université de Tunis El Manar, Tunis, Tunisia.
- 11Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
- 12Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, USA.
- 13Department of Microbiology, University of Alabama, Birmingham, USA.
- 14Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- 15Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- 16Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA.
- 17Massachusetts Institute of Technology, Cambridge, MA, USA.
- 18Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- 19Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. [email protected].
- 20Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. [email protected].
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.
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BibTeX
@article{teles2026identification,
title = {{Identification of a spatially organized TREM2-associated permissive macrophage niche in human pulmonary tuberculosis alveolar pneumonia.}},
author = {Rosane M B Teles and Chaouki Benabdessalem and Jonathan Perrie and Cenfu Wei and Julie West and Bruno J de Andrade Silva and Priscila R Andrade and Lilah A Mansky and Prajan Divaka and Linda Fischbacher and Karen Lam and Feiyang Ma and Yiqian Gu and Kimia Rategh and Madeline Brown and Aparna Pillai and Kapongo Lumamba and Threnesan Naidoo and Samuel M French and Emna Romdhane and Mohamed-Ridha Barbouche and Eynav Klechevsky and Marco Colonna and Adrie J C Steyn and Steven J Bensinger and Daniel L Barber and Soumaya Rammeh and Parambir S Dulai and Bryan D Bryson and Matteo Pellegrini and John T Belisle and Barry R Bloom and Robert L Modlin},
journal = {Nature communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76814-8},
url = {https://europepmc.org/article/MED/42875426},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of a spatially organized TREM2-associated permissive macrophage niche in human pulmonary tuberculosis alveolar pneumonia.
AU - Rosane M B Teles
AU - Chaouki Benabdessalem
AU - Jonathan Perrie
AU - Cenfu Wei
AU - Julie West
AU - Bruno J de Andrade Silva
AU - Priscila R Andrade
AU - Lilah A Mansky
AU - Prajan Divaka
AU - Linda Fischbacher
AU - Karen Lam
AU - Feiyang Ma
AU - Yiqian Gu
AU - Kimia Rategh
AU - Madeline Brown
AU - Aparna Pillai
AU - Kapongo Lumamba
AU - Threnesan Naidoo
AU - Samuel M French
AU - Emna Romdhane
AU - Mohamed-Ridha Barbouche
AU - Eynav Klechevsky
AU - Marco Colonna
AU - Adrie J C Steyn
AU - Steven J Bensinger
AU - Daniel L Barber
AU - Soumaya Rammeh
AU - Parambir S Dulai
AU - Bryan D Bryson
AU - Matteo Pellegrini
AU - John T Belisle
AU - Barry R Bloom
AU - Robert L Modlin
PY - 2026
DA - 2026/08/21
JO - Nature communications
DO - 10.1038/s41467-026-76814-8
UR - https://europepmc.org/article/MED/42875426
AB - 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.
SN - 2041-1723
ER -