Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium

Garnering Information on Granulomas In tuberculosis, the tuberculous granuloma has been viewed traditionally as a host-protective structure that serves to “wall off” mycobacteria. However, recent work in the zebrafish embryo showed that mycobacteria convert the nascent granuloma into a vehicle for bacterial expansion and dissemination. Thus, intercepting granuloma formation could provide a strategy for treating tuberculosis, an urgent public health goal in light of the epidemic of extensively drug-resistant tuberculosis. Now Volkman et al. (p. 466, published online 10 December; see the Perspective by Agarwal and Bishai) present the molecular pathway by which mycobacteria induce granulomas in zebrafish. Inhibition of this pathway attenuates infection by reducing granuloma formation, suggesting a therapeutic target for tuberculosis treatment. Epithelial cells play a role in tubercular granuloma formation and mycobacterial virulence. Granulomas, organized aggregates of immune cells, are a hallmark of tuberculosis and have traditionally been thought to restrict mycobacterial growth. However, analysis of Mycobacterium marinum in zebrafish has shown that the early granuloma facilitates mycobacterial growth; uninfected macrophages are recruited to the granuloma where they are productively infected by M. marinum. Here, we identified the molecular mechanism by which mycobacteria induce granulomas: The bacterial secreted protein 6-kD early secreted antigenic target (ESAT-6), which has long been implicated in virulence, induced matrix metalloproteinase–9 (MMP9) in epithelial cells neighboring infected macrophages. MMP9 enhanced recruitment of macrophages, which contributed to nascent granuloma maturation and bacterial growth. Disruption of MMP9 function attenuated granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy.