Thursday, May 15, 2025
5/15/2025
Genetic dissection of angiogenesis during mycobacterial infection - Abstract Mycobacterium tuberculosis kills approximately 1.5 million people annually. It has long been observed that the central structure of tuberculosis, the mycobacterial granuloma, can be extensively vascularized. However, the inciting stimulus and functional consequences of this vascularization have not been fully examined. Using a zebrafish mycobacterial infection model that recapitulates important aspects of human granulomas, we found that granuloma-induced angiogenesis coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfa. Interception of this pathway with clinically available inhibitors resulted in reduced burden, altered immune responses, and improved outcome. We found that a specific cyclopropane modification on the bacterial lipid trehalose dimycolate (TDM) is critical to granuloma- induced angiogenesis. We hypothesize that this specific bacterial lipid in combination with other secreted proteins drives or accelerates angiogenesis to the benefit of infecting mycobacteria. We will define the cellular and molecular mechanisms by which pathogenic mycobacteria promote the pro-angiogenic environment of mycobacterial granulomas to facilitate their own growth, dissemination and survival. We defined a specific subset of macrophages within the mycobacterial granuloma that respond to TDM, produce Vegfa, and induce angiogenesis. We will examine how TDM drives induction of the NFAT signaling pathway in vivo and the consequences to infection. Using single-cell sequencing, we found that epithelioid macrophages within the tuberculous granuloma produce large amounts of fibronectin. We will dissect how production of this ECM component influences angiogenesis and how secreted bacterial Ag85 binding to fibronectin modulates this response. Finally, we will assess how cell-autonomous regulation of the ApoA1 axis in infected macrophages leads to changes in angiogenesis, lipid availability, and immune response during mycobacterial infection. Ultimately, the modulation of host angiogenic pathways may provide new strategies for host-directed therapies for tuberculosis.
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