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

Abstract

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 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.

Pulmonary Mycobacterial Granuloma

“…Although our current study carries a focus on the host mechanisms, based on some recent evidence, 16 it is plausible to speculate that mycobacteria have adopted the mechanisms to fully parasitize the granuloma in an attempt to evade host-mediated clearance, and that some of these mechanisms may involve the works of the mycobacterial "persistence" gene products. 16,17 Many parallels exist between the granuloma and other immuneevasive microenvironments, such as those within tumors.…”

“…16,17 Many parallels exist between the granuloma and other immuneevasive microenvironments, such as those within tumors. The ability of the tumor to shield itself from immune infiltration is mediated by using many mechanisms similar to those seen after the formation of mycobacterial granuloma.…”

“…There is the evidence that by expressing a set of "persistence" genes, the mycobacterium, together with the host, contributes to granuloma formation as a mechanism to facilitate bacterial dissemination and persistence. 16,17 This suggests that the granuloma microenvironment is subject to immune subversive influences from mycobacteria throughout the course of infection.…”

Immunity and Immunopathology in the Tuberculous Granuloma

“…A better understanding of this chemotactic pathway came from a differential screen for host genes that are induced during wild-type but not DRD1 M. marinum infection in zebrafish larvae (Volkman et al 2010). Transcriptional induction of matrix metalloproteinase-9 (MMP9) was greater with wild-type than the DRD1 bacteria, and this difference was further amplified when MMP9-dependent gelatinase activity was assayed in vivo; wild-type infection induced robust MMP9-dependent gelatinase activity whereas DRD1 infection had barely any activity.…”

MMPs are regulatory enzymes in pathways of inflammatory disorders, tissue injury, malignancies and remodelling of the lung

“…The destruction of extracellular matrix by MMPs allows mycobacteria to spread from the interstitium to the airways, and results in cavities with an immunodeficient milieu in which mycobacteria can proliferate as a consequence of a missing protective immune response. These events are initiated by mycobacterial MMP activation within the monocytes/macrophages hosting the mycobacteria in the pulmonary interstitium, as discussed by ELKINGTON et al [6] in a forthcoming article in this series, and elsewhere [7].…”