Abstract
Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM) are acid-fast bacilli that trigger granuloma formation, a hallmark immune response aimed at containing infection. While the biology of Mtb granulomas has been widely investigated, far less is known about granulomas caused by NTM infection, despite the increasing prevalence and clinical challenge of NTM cases worldwide. Because granulomas influence infection control, pathology, and treatment response, understanding their cellular organization and signaling is critical to improving therapeutic strategies. Therefore, we characterized granulomas formed following infection of rhesus macaques with Mycobacterium avium subsp. hominissuis (MAH) and compared them to granulomas from cynomolgus macaques infected with Mtb. MAH-associated granulomas were enriched in pro-inflammatory macrophages and, within granulomatous regions, both immune and non-immune cells exhibited pronounced inflammatory transcriptional signatures. By contrast, cells in non-granulomatous tissue displayed signatures associated with regulatory, wound-healing responses. Mtb granulomas were overall more inflammatory than MAH granulomas but showed diminished evidence of adaptive immune activation, cellular survival pathways, and signals supporting granuloma structural integrity. Notably, endothelial cells, fibroblasts, and a subset of macrophages were primary drivers of the signaling differences between Mtb and MAH granulomas. These findings highlight fundamental distinctions in granuloma biology between tuberculosis and nontuberculous infections. The reduced adaptive immune signatures and altered survival signaling seen in Mtb granulomas may underlie its aggressive pathology, while MAH granulomas’ distinct macrophage and stromal cell responses may contribute to the chronic, difficult-to-treat nature of this disease. Recognizing these differences could inform targeted therapies and strategies to better manage both tuberculous and nontuberculous infections.
Document Type
Article
Publication Date
2026
Digital Object Identifier (DOI)
https://doi.org/10.3389/fmicb.2025.1741883
Funding Information
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the NIH (R01AI152258-04), the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558), the University of Kentucky Arts & Sciences Imaging Center, and the University of Kentucky Center for Computational Sciences and Information Technology Services Morgan Compute Cluster.
Repository Citation
Doratt, Brianna M.; Napier, Ethan G.; Boroujeni, Mahdi Eskandarian; Douglas, Sarah; Davies, Michael H.; Bermudez, Luiz; Spindel, Eliot; McCaffrey, Erin F.; and Messaoudi, Ilhem, "Granulomatous cellular signatures in nontuberculous and tuberculous mycobacterial infections" (2026). Microbiology, Immunology, and Molecular Genetics Faculty Publications. 200.
https://uknowledge.uky.edu/microbio_facpub/200
Notes/Citation Information
© 2026 Doratt, Napier, Boroujeni, Douglas, Davies, Bermudez, Spindel, McCaffrey and Messaoudi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.