Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection.
During mycobacterial infections, pathogenic mycobacteria manipulate both host immune and stromal cells to establish and maintain a productive infection. In humans, non-human primates, and zebrafish models of infection, pathogenic mycobacteria produce and modify the specialized lipid trehalose 6,6'-dimycolate (TDM) in the bacterial cell envelope to drive host angiogenesis toward the site of forming granulomas, leading to enhanced bacterial growth. Here, we use the zebrafish-Mycobacterium marinum infection model to define the signaling basis of the host angiogenic response. Through intravital imaging and cell-restricted peptide-mediated inhibition, we identify macrophage-specific activation of NFAT signaling as essential to TDM-mediated angiogenesis in vivo. Exposure of cultured human cells to Mycobacterium tuberculosis results in robust induction of VEGFA, which is dependent on a signaling pathway downstream of host TDM detection and culminates in NFATC2 activation. As granuloma-associated angiogenesis is known to serve bacterial-beneficial roles, these findings identify potential host targets to improve tuberculosis disease outcomes.
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Related Subject Headings
- Zebrafish
- Tuberculosis
- Signal Transduction
- NFATC Transcription Factors
- Mycobacterium tuberculosis
- Mycobacterium marinum
- Macrophages
- Humans
- Granuloma
- Animals
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Zebrafish
- Tuberculosis
- Signal Transduction
- NFATC Transcription Factors
- Mycobacterium tuberculosis
- Mycobacterium marinum
- Macrophages
- Humans
- Granuloma
- Animals