# Genetic dissection of angiogenesis during mycobacterial infection

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $479,130

## Abstract

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.

## Key facts

- **NIH application ID:** 10765683
- **Project number:** 5R01AI125517-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** David M. Tobin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,130
- **Award type:** 5
- **Project period:** 2017-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765683

## Citation

> US National Institutes of Health, RePORTER application 10765683, Genetic dissection of angiogenesis during mycobacterial infection (5R01AI125517-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765683. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*