Macrophage NFAT Signaling Drives Angiogenesis in Response to Mycobacterial Infection


Identification: Brewer-William


Description

Macrophage NFAT Signaling Drives Angiogenesis in Response to Mycobacterial Infection
Through extensive co-evolution with their obligate hosts, mycobacteria have developed diverse mechanisms of subverting potentially curative host immune responses. One method of subversion is the induction of host angiogenesis at the site of infection, which could act in an either host-beneficial or host-detrimental manner. This angiogenesis has been demonstrated to provide a benefit to the bacteria, suggesting that the bacteria may specifically induce this process to its own advantage. We recently demonstrated that a specific modification on the mycobacterial glycolipid trehalose 6-6’-dimycolate (TDM) is required for robust mycobacteria-induced angiogenesis. This proposal seeks to identify the underlying signaling mechanisms for the induction of this angiogenesis through genetic dissection of host response pathways. Through the specific identification of host receptors and signaling pathways that respond to TDM, we will reveal novel mechanisms by which pathogenic mycobacteria subvert the host immune response and more thoroughly characterize the biology of the host-pathogen interaction at the granuloma. This proposal will focus on addressing the mechanisms of first detection of TDM by a surface C-type lectin receptor and the downstream signaling events through NFAT to direct angiogenesis. We have developed a sterile injection model for TDM to assess the in vivo role for this bacterial glycolipid in the induction of angiogenesis. We will make use of novel host genetic reagents to probe how this specific bacterial cell wall lipid engages the host to drive angiogenesis and the functional consequences of modulating these macrophage signaling pathways on host outcome.

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