Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection

Mycobacterium tuberculosis infection in humans triggers formation of granulomas, tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. We find that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. Using the zebrafish-Mycobacterium marinum model, we identify fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function results in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. In humans, we find that granuloma macrophages are similarly transformed. Long considered largely through the prism of immune signaling pathways, granuloma macrophages are reprogrammed by epithelial modules that alter the trajectory of mycobacterial infection. We found that mycobacterial granuloma formation was accompanied by epithelialization within the granuloma. To further assess the epithelial reprogramming within granuloma macrophages, granulomas were microdissected from 2 week post infection zebrafish infected with 400 CFU M. marinum. Dissected granulomas were compared to matched macrophage samples sorted from the kidney of infected animals. Control cell populations were also derived from mixed larval cell populations specifically depleted for macrophages. Data was analyzed from 5 granuloma samples, 4 kidney macrophage samples and 3 control cell populations. Granuloma samples were derived from 2-7 granuloma dissected from a single animal. Macrophage populations were derived from matched kidneys of the granuloma-containing animals.