Identification of a spatially organized TREM2-associated permissive macrophage niche in human pulmonary tuberculosis alveolar pneumonia
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Rosane M. B. Teles, Chaouki Benabdessalem, Jonathan Perrie, Cenfu Wei, Julie West, Bruno J. de Andrade Silva, Priscila R. Andrade, Lilah A. Mansky, Prajan Divaka, Linda Fischbacher, Karen Lam, Feiyang Ma, Yiqian Gu, Kimia Rategh, Madeline Brown, Aparna Pillai, Kapongo Lumamba, Threnesan Naidoo, Samuel M. French, Emna Romdhane, Mohamed-Ridha Barbouche, Eynav Klechevsky, Marco Colonna, Adrie J. C. Steyn, Steven J. Bensinger, Daniel L. Barber, Soumaya Rammeh, Parambir S. Dulai, Bryan D. Bryson, Matteo Pellegrini, John T. Belisle, Barry R. Bloom, Robert L. Modlin
Institutions: University of California, Los Angeles, Tunis University, Institut Pasteur de Tunis, Tunis El Manar University, Northwestern University, Colorado State University, Africa Health Research Institute, Walter Sisulu University, Hôpital Charles-Nicolle, Faculté de médecine de Tunis, Arabian Gulf University, Washington University in St. Louis, University of Alabama at Birmingham, National Institute of Allergy and Infectious Diseases, Massachusetts Institute of Technology, Harvard University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7203859366
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