Macrophage Reprogramming During Granuloma Formation in the Zebrafish

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Abstract Granulomas form as a conserved host response to a variety of inflammatory and infectious stimuli. As granulomas assemble, macrophages interdigitate and undergo a striking morphological transition, taking on an epithelioid appearance. The basis for this transformation and the consequences to disease are not well understood. We identified a conserved reprogramming of macrophages that underlies the assembly and stability of mycobacterial granulomas. Using a zebrafish model, we find that broad epithelial modules and structures are induced during tuberculous granuloma formation and are critical for granuloma integrity. In this project we will 1) assess how specific Type 2 immune signals interact with countervailing Type 1 signals to coordinate epithelioid transformation and granuloma assembly; 2) test the role of the EMP2/Focal Adhesion Kinase (FAK) pathway in granuloma stability, disaggregation and the dissemination of infection; 3) based on scRNA-seq analysis of granulomas as well as macrophages isolated from individual animals, assess the role of JAG1-Notch in granuloma formation, maintenance, and infection trajectory. We will extend findings from these studies into analysis of human disease. Overall, this proposal will test the hypothesis that, in a striking parallel to mesenchymal-to-epithelial transitions in development and cancer, macrophages draw on classical developmental signaling pathways to undergo an epithelial-like transition. This reprogramming underlies the central structure of tuberculosis and defines interactions with the host immune system. We will test how perturbations of these pathways lead to alterations in disease progression and outcome. A new perspective on this critical structure may have important implications for our understanding of disease progression and provides opportunities for new therapeutic approaches.