Tuberculous granulomas are highly organized structures that form upon infection with a member of the Mycobacterium tuberculosis complex (MTBC) or close relatives like M. marinum. Granulomas act as a double-edged sword: they contain infection but can also enable bacterial expansion and limit antibiotic penetration. The central scaffold of the granuloma is a layer of epithelioid macrophages that shields the necrotic core, harboring the bulk of the bacterial burden away from immune cells and antibiotics that struggle to penetrate this structure. The transcription factor STAT6 has been shown to be vital for the epithelioid transformation of macrophages and necrotic granuloma formation through upstream IL4R signaling (Cronan et al. Cell 2021). Here, we investigate the cellular reservoirs of IL4 and IL13 within the granuloma and the contribution of each of these cytokines to granuloma formation and mycobacterial pathogenesis.
Goal: To delineate the role of IL4 and IL13 signaling in to the development and architecture of tuberculous granulomas, and assess these pathways as novel adjunct host-directed therapies.
We employed a zebrafish (Danio rerio)-M. marinum infection model, which closely mimics human tuberculosis pathology. Genetically modified zebrafish were used to disrupt IL4, IL13 or IL4/IL13 signaling. Histological and immunofluorescence staining were used to monitor granuloma organization and the induction and spatial distribution of IL4/IL13 throughout chronic mycobacterial infection. The functional outcomes of altered IL4/IL13 signaling were assessed by bacterial number within these hosts.
We expect to identify the significance of IL4/IL13 signaling within the granuloma and the role of the signals in the overall trajectory of mycobacterial infection. These findings will be critical to understanding the immunological mechanisms governing granuloma formation. As granulomas act as a substantial barrier to the effective treatment of mycobacterial infection, these insights could offer novel treatment approaches through modulation of granuloma formation and function.