title: Infection-Induced Vascular Permeability Aids Mycobacterial Growth.
abstract: 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.
authors: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.|Tuberculosis Research Program, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, The University of Sydney, Newtown, NSW, Australia.
authors: Stefan H
authors: SH
authors: Oehlers
authors: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
authors: Mark R
authors: MR
authors: Cronan
authors: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
authors: Rebecca W
authors: RW
authors: Beerman
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: Matthew G
authors: MG
authors: Johnson
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: Jianhua
authors: J
authors: Huang
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: Christopher D
authors: CD
authors: Kontos
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: Jason E
authors: JE
authors: Stout
authors: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
authors: David M
authors: DM
authors: Tobin
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002199:Capillary Permeability; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006099:Granuloma / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007814:Larva; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D009161:Mycobacterium / Q000187:drug effects / Q000254:growth & development*; D009164:Mycobacterium Infections / Q000473:pathology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction; D014376:Tuberculosis / Q000382:microbiology; D015027:Zebrafish
chemical_list: D042702:Angiopoietin-2; D042787:Receptor, TIE-2
keywords: Mycobacterium tuberculosis; TIE2; VE-PTP; angiopoietin; granuloma; vascular permeability; zebrafish