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

• Published in: Cell host & microbe Vol. 24; no. 4; pp. 514 - 525.e6
• Main Authors: Walton, Eric M., Cronan, Mark R., Cambier, C.J., Rossi, Andrea, Marass, Michele, Foglia, Matthew D., Brewer, W. Jared, Poss, Kenneth D., Stainier, Didier Y.R., Bertozzi, Carolyn R., Tobin, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2018
• Subjects: angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cord Factors - metabolism; Disease Models, Animal; granuloma; host-directed therapy; Humans; Indazoles; macrophage; 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; PcaA; 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; trehalose dimycolate; Tuberculoma - immunology; Tuberculoma - microbiology; Tuberculoma - pathology; tuberculosis; vegf; Zebrafish; angiogenesis; PcaA; tuberculosis; granuloma; vegf; macrophage; host-directed therapy; zebrafish; trehalose dimycolate
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2018.09.004

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. [Display omitted] •Mycobacterial granuloma angiogenesis requires the cell wall glycolipid TDM•The mycobacterial enzyme PcaA promotes angiogenesis via cis-cyclopropanation of TDM•Cyclopropanated TDM induces granuloma vascularization through activating Vegfa signaling•pcaA mutation or Vegfa pathway blockade reduces bacterial growth in vivo Granuloma formation during tuberculosis is accompanied by remodeling of host vasculature. Walton et al. identify the mycobacterial enzyme PcaA, which catalyzes proximal cis-cyclopropanation of trehalose dimycolate, as an important determinant of granuloma-associated angiogenesis. This form of trehalose dimycolate induces Vegfa-mediated angiogenesis at the granuloma, promoting bacterial growth.