The granuloma serves not only as a physical barrier to restrict the dissemination of intracellular pathogens but also functions as a complex immune microenvironment. However, the bioenergetics and regulatory mechanisms maintaining this architecture remain elusive in vertebrates. Here, integrating multi-tissue transcriptomics, single-cell RNA sequencing (scRNA-seq), ultrastructural imaging, and fluorescence in situ hybridization (FISH) in a largemouth bass ( Micropterus salmoides )– Nocardia seriolae infection model, we resolved the metabolic and functional landscape of the granuloma. We found that across multiple tissues (head kidney, spleen, liver, kidney), the host initiates a synchronized transcriptional program that promotes macrophage differentiation into specialized epithelioid macrophages (E-Macs). Notably, E-Macs concurrently upregulated specific transporters and metabolic enzymes (e.g., laao , slc6a8 ), as well as oxidative phosphorylation (OXPHOS) and glycolysis genes, accompanied by mitochondrial proliferation. Functionally, E-Macs shifted from a pro-inflammatory to an immunoregulatory and pro-survival phenotype, characterized by high expression of protease inhibitors (e.g., csta ) and anti-apoptotic factors (e.g., bcl2l14 , ywhag1 ). Comparative analysis in zebrafish confirmed these metabolic and regulatory signatures are evolutionarily conserved. In conclusion, this study reveals a host survival strategy of immune regulation underpinned by metabolic adaptation, providing novel perspectives for controlling chronic granulomatous diseases in aquaculture. • Multi-tissue transcriptomics reveal a synchronized granuloma program. • Epithelioid macrophages exhibit dual metabolic activation of OXPHOS and glycolysis. • An immunoregulatory phenotype underpins long-term barrier maintenance. • Granuloma metabolic and regulatory programs are conserved in teleosts.
Zhou et al. (Fri,) studied this question.