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ZFIN ID: ZDB-PUB-181012-16
Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling
Walton, E.M., Cronan, M.R., Cambier, C.J., Rossi, A., Marass, M., Foglia, M.D., Brewer, W.J., Poss, K.D., Stainier, D.Y.R., Bertozzi, C.R., Tobin, D.M.
Date: 2018
Source: Cell Host & Microbe   24: 514-525.e6 (Journal)
Registered Authors: Cambier, CJ, Cronan, Mark, Foglia, Matthew, Poss, Kenneth D., Stainier, Didier, Tobin, David
Keywords: PcaA, angiogenesis, granuloma, host-directed therapy, macrophage, trehalose dimycolate, tuberculosis, vegf, zebrafish
MeSH Terms:
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Bacterial Proteins/genetics
  • Bacterial Proteins/metabolism*
  • Cord Factors/metabolism
  • Disease Models, Animal
  • Humans
  • Macrophages/immunology
  • Macrophages/microbiology
  • Methyltransferases/genetics
  • Methyltransferases/metabolism*
  • Mycobacterium Infections, Nontuberculous/immunology
  • Mycobacterium Infections, Nontuberculous/microbiology
  • Mycobacterium marinum/enzymology*
  • Mycobacterium marinum/genetics
  • Mycobacterium marinum/pathogenicity
  • Mycolic Acids/metabolism
  • Neovascularization, Pathologic/immunology
  • Neovascularization, Pathologic/microbiology*
  • Neovascularization, Pathologic/pathology
  • Pyrimidines/pharmacology
  • Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor/drug effects
  • Receptors, Vascular Endothelial Growth Factor/metabolism*
  • Signal Transduction
  • Sulfonamides/pharmacology
  • Tuberculoma/immunology
  • Tuberculoma/microbiology*
  • Tuberculoma/pathology
  • Zebrafish
PubMed: 30308157 Full text @ Cell Host Microbe
FIGURES
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.
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