Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Walton, EM; Cronan, MR; Cambier, CJ; Rossi, A; Marass, M; Foglia, MD; Brewer, WJ; Poss, KD; Stainier, DYR; Bertozzi, CR; Tobin, DM

Published Date

  • October 2018

Published In

Volume / Issue

  • 24 / 4

Start / End Page

  • 514 - 525.e6

PubMed ID

  • 30308157

Pubmed Central ID

  • 30308157

Electronic International Standard Serial Number (EISSN)

  • 1934-6069

International Standard Serial Number (ISSN)

  • 1931-3128

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2018.09.004

Language

  • eng