Abstract
Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis. Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations. Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Antibiotics, Antitubercular / pharmacology
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Bacterial Load / drug effects
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Disease Models, Animal
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Drug Synergism
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Granuloma / drug therapy
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Granuloma / metabolism
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Granuloma / microbiology
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Granuloma / pathology
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Hypoxia / metabolism
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Hypoxia / microbiology
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Hypoxia / pathology
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Larva / drug effects
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Larva / microbiology
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Macrophages / metabolism
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Macrophages / microbiology
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Macrophages / pathology
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Mycobacterium Infections, Nontuberculous / drug therapy
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Mycobacterium Infections, Nontuberculous / metabolism
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Mycobacterium Infections, Nontuberculous / microbiology*
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Mycobacterium Infections, Nontuberculous / pathology
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Mycobacterium marinum / drug effects*
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Mycobacterium marinum / growth & development*
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Mycobacterium marinum / pathogenicity
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / microbiology*
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Signal Transduction / drug effects*
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Tuberculosis / drug therapy
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Tuberculosis / microbiology
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Tuberculosis / pathology
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism
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Zebrafish / growth & development
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Zebrafish / microbiology*
Substances
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Angiogenesis Inhibitors
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Antibiotics, Antitubercular
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Vascular Endothelial Growth Factor A
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Receptors, Vascular Endothelial Growth Factor