Infection-Induced Vascular Permeability Aids Mycobacterial Growth

• Published in: The Journal of infectious diseases Vol. 215; no. 5; pp. 813 - 817
• Main Authors: Oehlers, Stefan H., Cronan, Mark R., Beerman, Rebecca W., Johnson, Matthew G., Huang, Jianhua, Kontos, Christopher D., Stout, Jason E., Tobin, David M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2017
• Subjects: Angiopoietin-2 - genetics; Angiopoietin-2 - metabolism; Animals; Animals, Genetically Modified; Brief Report; Capillary Permeability; Disease Models, Animal; Gene Expression Regulation; Granuloma - microbiology; Host-Pathogen Interactions; Humans; Larva; Macrophages - drug effects; Macrophages - microbiology; Mycobacterium - drug effects; Mycobacterium - growth & development; Mycobacterium Infections - pathology; PATHOGENESIS AND HOST RESPONSE; Receptor, TIE-2 - metabolism; Signal Transduction; Tuberculosis - microbiology; Zebrafish; Mycobacterium tuberculosis; TIE2; granuloma; zebrafish; vascular permeability; VE-PTP; angiopoietin
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiw355

Pathogenic mycobacteria trigger formation of organized granulomas. As granulomas mature, they induce angiogenesis and vascular permeability. Here, in a striking parallel to tumor pro-angiogenic signaling, we identify angiopoietin-2 (ANG-2) induction as an important component of vascular dysfunction during mycobacterial infection. Mycobacterial infection in humans and zebrafish results in robust induction of ANG-2 expression from macrophages and stromal cells. Using a small-molecule inhibitor closely related to one currently in clinical trials, we link ANG-2/TIE2 signaling to vascular permeability during mycobacterial infection. Targeting granuloma-induced vascular permeability via vascular endothelial-protein tyrosine phosphatase inhibition limits mycobacterial growth, suggesting a new strategy for host-directed therapies against tuberculosis.