ABSTRACT Angiogenesis is a central feature of the host immune response to mycobacterial infection, but the mechanisms by which this angiogenesis is produced remain understudied. We now know that mycobacterial infection specifically induces this angiogenic response, which provides benefit to the bacteria, through an unusual modification of a cell wall glycolipid. This glycolipid, trehalose 6-6’-dimycolate (TDM) is cis-cyclopropanated by the mycobacterial enzyme pcaA along its C50+ fatty acid tails, which allows it to specifically induce the induction of VEGF. While the connection between infection, host exposure to TDM, and the ultimately VEGF-dependent angiogenic response have become clearer, the mechanisms by which the host detects TDM and the subsequent intracellular signaling events leading to vegfaa transcription remain unknown. This proposal will utilize the zebrafish-Mycobacterium marinum model system to identify the underlying signaling mechanisms through the genetic dissection of this natural host-pathogen system. We will identify specific host receptors and signaling pathways that respond to TDM, revealing novel mechanisms by which pathogenic mycobacteria subvert the host immune response and characterize the biology of the host-pathogen interface at the granuloma. We will focus first on promising preliminary results implicating NFAT signaling in the induction of the angiogenic response, dissecting the role of this previously underappreciated pathway in the host response to mycobacteria. Additionally, we have identified novel C-type lectin receptor homologs in the zebrafish that will allow us to draw new connections between C-type lectin signaling and angiogenesis. We have developed novel genetic reagents that will allow us to probe how this specific bacterial cell wall lipid engages the host to drive angiogenesis and identify the functional consequences of modulating these macrophage signaling pathways on host outcome.