# Macrophage Signaling Pathways Orchestrating Mycobacteria-induced Angiogenesis

> **NIH NIH F31** · DUKE UNIVERSITY · 2021 · $38,075

## Abstract

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.

## Key facts

- **NIH application ID:** 10314484
- **Project number:** 1F31HL160329-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** William Jared Brewer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,075
- **Award type:** 1
- **Project period:** 2021-09-28 → 2022-09-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314484

## Citation

> US National Institutes of Health, RePORTER application 10314484, Macrophage Signaling Pathways Orchestrating Mycobacteria-induced Angiogenesis (1F31HL160329-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10314484. Licensed CC0.

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