SPIC-dependent erythrophagocytic macrophages drive granuloma formation and pathogen persistence during intracellular bacterial infection

Macrophages maintain tissue homeostasis by phagocytosing spent cells, recycling nutrients, and mounting antimicrobial responses to eliminate pathogens. Yet, they can also act as a cellular niche and organize granulomas that enable intracellular bacteria, such as Salmonella enterica , to persist in infected tissues. Here, using a murine Salmonella Typhimurium ( S Tm) infection model, we find that granuloma formation and bacterial persistence are dependent on SPIC, which controls development of VCAM1 ⁺ macrophages critical for erythrocyte, heme, and iron recycling. VCAM1 ⁺ macrophages markedly increase in infected spleens and have high levels of erythrophagocytosis, intracellular bacteria, and T-cell co-stimulatory ligands. Using SPIC-deficient mice generated from CRISPR gene editing, we show that SPIC is required for macrophage co-stimulatory ligand expression and formation of a VCAM1 ⁺ macrophage zone that produces CXCL9 retaining T cells at the granuloma periphery. SPIC deletion abolishes this granuloma cellular architecture and reduces bacterial persistence. We propose that SPIC-dependent erythrophagocytic macrophages drive granuloma formation and bacterial tissue persistence.