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Nature. 2015 Jan 29;517(7536):612-5. doi: 10.1038/nature13967. Epub 2014 Nov 24.

Interception of host angiogenic signalling limits mycobacterial growth.

Author information

1
Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1023, New Zealand.

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.

PMID:
25470057
PMCID:
PMC4312197
DOI:
10.1038/nature13967
[Indexed for MEDLINE]
Free PMC Article

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