Infection-Induced Vascular Permeability Aids Mycobacterial Growth

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...

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Published inThe Journal of infectious diseases Vol. 215; no. 5; pp. 813 - 817
Main Authors Oehlers, Stefan H., Cronan, Mark R., Beerman, Rebecca W., Johnson, Matthew G., Huang, Jianhua, Kontos, Christopher D., Stout, Jason E., Tobin, David M.
Format Journal Article
LanguageEnglish
Published United States Oxford University Press 01.03.2017
Subjects
Angiopoietin-2 - genetics
Angiopoietin-2 - metabolism
Animals
Animals, Genetically Modified
Brief Report
Capillary Permeability
Disease Models, Animal
Gene Expression Regulation
Granuloma - microbiology
Host-Pathogen Interactions
Humans
Larva
Macrophages - drug effects
Macrophages - microbiology
Mycobacterium - drug effects
Mycobacterium - growth & development
Mycobacterium Infections - pathology
PATHOGENESIS AND HOST RESPONSE
Receptor, TIE-2 - metabolism
Signal Transduction
Tuberculosis - microbiology
Zebrafish
Mycobacterium tuberculosis
TIE2
granuloma
zebrafish
vascular permeability
VE-PTP
angiopoietin
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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.
AbstractList 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.
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.
Author Kontos, Christopher D.
Oehlers, Stefan H.
Cronan, Mark R.
Tobin, David M.
Huang, Jianhua
Johnson, Matthew G.
Beerman, Rebecca W.
Stout, Jason E.
AuthorAffiliation 1 Department of Molecular Genetics and Microbiology
4 Tuberculosis Research Program , Centenary Institute , Camperdown
3 Department of Immunology , Duke University School of Medicine , Durham, North Carolina
5 Sydney Medical School, The University of Sydney, Newtown, Australia
2 Department of Medicine
AuthorAffiliation_xml – name: 1 Department of Molecular Genetics and Microbiology
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– name: 4 Tuberculosis Research Program , Centenary Institute , Camperdown
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Copyright Copyright © 2017 Oxford University Press on behalf of the Infectious Diseases Society of America
The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. 2016
The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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– notice: The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. 2016
– notice: The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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Keywords Mycobacterium tuberculosis
TIE2
granuloma
zebrafish
vascular permeability
VE-PTP
angiopoietin
Language English
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Presented in part: Zebrafish Disease Models Conference, Boston, Massachusetts, 24–27 August 2015; Tuberculosis Co-Morbidities and Immunopathogenesis Keystone Symposium, Keystone, Colorado, 28 February–3 March 2016.
Correspondence: D. M. Tobin, Department of Molecular Genetics and Microbiology, Duke University School of Medicine, DUMC 3020, Durham, NC 27710 (david.tobin@duke.edu).
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Snippet Pathogenic mycobacteria trigger formation of organized granulomas. As granulomas mature, they induce angiogenesis and vascular permeability. Here, in a...
Abstract Pathogenic mycobacteria trigger formation of organized granulomas. As granulomas mature, they induce angiogenesis and vascular permeability. Here, in...
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SubjectTerms Angiopoietin-2 - genetics
Angiopoietin-2 - metabolism
Animals
Animals, Genetically Modified
Brief Report
Capillary Permeability
Disease Models, Animal
Gene Expression Regulation
Granuloma - microbiology
Host-Pathogen Interactions
Humans
Larva
Macrophages - drug effects
Macrophages - microbiology
Mycobacterium - drug effects
Mycobacterium - growth & development
Mycobacterium Infections - pathology
PATHOGENESIS AND HOST RESPONSE
Receptor, TIE-2 - metabolism
Signal Transduction
Tuberculosis - microbiology
Zebrafish
Title Infection-Induced Vascular Permeability Aids Mycobacterial Growth
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