1. Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling.
- Author
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Walton EM, Cronan MR, Cambier CJ, Rossi A, Marass M, Foglia MD, Brewer WJ, Poss KD, Stainier DYR, Bertozzi CR, and Tobin DM
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Bacterial Proteins genetics, Cord Factors metabolism, Disease Models, Animal, Humans, Indazoles, Macrophages immunology, Macrophages microbiology, Methyltransferases genetics, Mycobacterium Infections, Nontuberculous immunology, Mycobacterium Infections, Nontuberculous microbiology, Mycobacterium marinum genetics, Mycobacterium marinum pathogenicity, Mycolic Acids metabolism, Neovascularization, Pathologic immunology, Neovascularization, Pathologic pathology, Pyrimidines pharmacology, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor drug effects, Signal Transduction, Sulfonamides pharmacology, Tuberculoma immunology, Tuberculoma pathology, Zebrafish, Bacterial Proteins metabolism, Methyltransferases metabolism, Mycobacterium marinum enzymology, Neovascularization, Pathologic microbiology, Receptors, Vascular Endothelial Growth Factor metabolism, Tuberculoma microbiology
- Abstract
Mycobacterial infection leads to the formation of characteristic immune aggregates called granulomas, a process accompanied by dramatic remodeling of the host vasculature. As granuloma angiogenesis favors the infecting mycobacteria, it may be actively promoted by bacterial determinants during infection. Using Mycobacterium marinum-infected zebrafish as a model, we identify the enzyme proximal cyclopropane synthase of alpha-mycolates (PcaA) as an important bacterial determinant of granuloma-associated angiogenesis. cis-Cyclopropanation of mycobacterial mycolic acids by pcaA drives the activation of host Vegf signaling within granuloma macrophages. Cyclopropanation of the mycobacterial cell wall glycolipid trehalose dimycolate is both required and sufficient to induce robust host angiogenesis. Inducible genetic inhibition of angiogenesis and Vegf signaling during granuloma formation results in bacterial growth deficits. Together, these data reveal a mechanism by which PcaA-mediated cis-cyclopropanation of mycolic acids promotes bacterial growth and dissemination in vivo by eliciting granuloma vascularization and suggest potential approaches for host-directed therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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