Interception of host angiogenic signalling limits mycobacterial growth

Oehlers, Stefan H., Cronan, Mark R., Scott, Ninecia R., Thomas, Monica I., Okuda, Kazuhide S., Walton, Eric M., Beerman, Rebecca W., Crosier, Philip S. and Tobin, David M. (2015) Interception of host angiogenic signalling limits mycobacterial growth. Nature, 517 7536: 612-615. doi:10.1038/nature13967


Author Oehlers, Stefan H.
Cronan, Mark R.
Scott, Ninecia R.
Thomas, Monica I.
Okuda, Kazuhide S.
Walton, Eric M.
Beerman, Rebecca W.
Crosier, Philip S.
Tobin, David M.
Title Interception of host angiogenic signalling limits mycobacterial growth
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
0028-0836
Publication date 2015-01-29
Sub-type Article (original research)
DOI 10.1038/nature13967
Open Access Status Not yet assessed
Volume 517
Issue 7536
Start page 612
End page 615
Total pages 4
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis1, 2. 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 tuberculosis2. 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 populations3. 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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