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Interception of host angiogenic signalling limits mycobacterial growth.

Publication ,  Journal Article
Oehlers, SH; Cronan, MR; Scott, NR; Thomas, MI; Okuda, KS; Walton, EM; Beerman, RW; Crosier, PS; Tobin, DM
Published in: Nature
January 29, 2015

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

January 29, 2015

Volume

517

Issue

7536

Start / End Page

612 / 615

Location

England

Related Subject Headings

  • Zebrafish
  • Vascular Endothelial Growth Factor A
  • Tuberculosis
  • Signal Transduction
  • Receptors, Vascular Endothelial Growth Factor
  • Neovascularization, Pathologic
  • Mycobacterium marinum
  • Mycobacterium Infections, Nontuberculous
  • Macrophages
  • Larva
 

Citation

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Oehlers, S. H., Cronan, M. R., Scott, N. R., Thomas, M. I., Okuda, K. S., Walton, E. M., … Tobin, D. M. (2015). Interception of host angiogenic signalling limits mycobacterial growth. Nature, 517(7536), 612–615. https://doi.org/10.1038/nature13967
Oehlers, Stefan H., Mark R. Cronan, Ninecia R. Scott, Monica I. Thomas, Kazuhide S. Okuda, Eric M. Walton, Rebecca W. Beerman, Philip S. Crosier, and David M. Tobin. “Interception of host angiogenic signalling limits mycobacterial growth.Nature 517, no. 7536 (January 29, 2015): 612–15. https://doi.org/10.1038/nature13967.
Oehlers SH, Cronan MR, Scott NR, Thomas MI, Okuda KS, Walton EM, et al. Interception of host angiogenic signalling limits mycobacterial growth. Nature. 2015 Jan 29;517(7536):612–5.
Oehlers, Stefan H., et al. “Interception of host angiogenic signalling limits mycobacterial growth.Nature, vol. 517, no. 7536, Jan. 2015, pp. 612–15. Pubmed, doi:10.1038/nature13967.
Oehlers SH, Cronan MR, Scott NR, Thomas MI, Okuda KS, Walton EM, Beerman RW, Crosier PS, Tobin DM. Interception of host angiogenic signalling limits mycobacterial growth. Nature. 2015 Jan 29;517(7536):612–615.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

January 29, 2015

Volume

517

Issue

7536

Start / End Page

612 / 615

Location

England

Related Subject Headings

  • Zebrafish
  • Vascular Endothelial Growth Factor A
  • Tuberculosis
  • Signal Transduction
  • Receptors, Vascular Endothelial Growth Factor
  • Neovascularization, Pathologic
  • Mycobacterium marinum
  • Mycobacterium Infections, Nontuberculous
  • Macrophages
  • Larva