Mycobacterium tuberculosis kills approximately 1.5 million people annually. It has long been observed that mycobacterial granulomas can be extensively vascularized, but the functional consequences of this vascularization have not been fully examined. Using a zebrafish mycobacterial infection model that recapitulates important aspects of human mycobacterial granulomas, we found that granuloma-induced angiogenesis coincides with the generation of local hypoxia and transcriptional induction of the canonical pro- angiogenic molecule Vegfa. Interception of this pathway with clinically used inhibitors resulted in reduced burden and improved outcome. Building on our preliminary data that suggest a role for the VEGF pathway and the bacterial lipid trehalose dimycolate, we will define the cellular and molecular mechanisms by which pathogenic mycobacteria promote the pro-angiogenic environment of mycobacterial granulomas to facilitate their own growth, dissemination and survival. We also will probe the role of a parallel canonical angiogenic signaling pathway ? the angiopoietin/Tie2 pathway ? for which we have identified a novel host-directed drug that we have shown to be effective in reducing mycobacterial burden in zebrafish. Finally, we will build on our recent data showing induction of these pathways in human granuloma specimens and probe the functional effects of human genetic variants in mycobacterial infection. Overall, this proposal tests the hypothesis that, in a striking parallel to tumor biology, the interplay of angiogenesis, hypoxia and compromised vasculature contributes to mycobacterial pathogenesis. Ultimately, the modulation of these pathways may provide new strategies for host- directed therapies for tuberculosis.

Public Health Relevance

This project will investigate the observation that blood vessels remodel and grow toward the site of tuberculosis infections. Drugs that inhibit this process in animal models improve outcomes, as infecting bacteria are less able to access the oxygen they need for optimal growth. This project seeks to understand specific mechanisms by which infecting mycobacteria induce this process and to examine the effects of limiting vascular dysfunction for the host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI125517-01A1
Application #
9310873
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Eichelberg, Katrin
Project Start
2017-02-15
Project End
2022-01-31
Budget Start
2017-02-15
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$397,500
Indirect Cost
$147,500
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Cronan, Mark R; Matty, Molly A; Rosenberg, Allison F et al. (2018) An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nat Methods 15:1098-1107
Walton, Eric M; Cronan, Mark R; Cambier, C J et al. (2018) Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling. Cell Host Microbe 24:514-525.e6
Jain, Sanjay K; Tobin, David M; Tucker, Elizabeth W et al. (2018) Tuberculous meningitis: a roadmap for advancing basic and translational research. Nat Immunol 19:521-525