(Provided by the applicant) Abstract: Recognizing that tuberculosis (TB) is still one of the leading causes of human death, the international health-community has set ambitious targets to control TB by 2050. Unfortunately, this target cannot be achieved with current tools and requires the development and use of better anti-TB drugs/vaccines. Since, Mycobacterium tuberculosis (M.tb.) adapts to a quiescent physiological state - "dormancy" - and successfully evades anti-TB drugs and host-immune responses for decades, understanding the kinetics of adaptive bacterial responses and the host-microenvironment is essential for developing better anti-TB drugs/vaccines. However, current tools for assessing bacterial-host kinetics in animal models are limited to analyzing postmortem tissues. Artifacts introduced during sacrifice/processing make them less reliable. Moreover, lesionspecific characteristics are generally not assessed separate from the whole organ. Since a different animal is sacrificed at every time-point, bacterial-lesion kinetics in an individual animal can also never be assessed. We have pioneered the development of imaging biomarkers to assess M.tb. bacterial burden in animal models. In this proposal, we will develop novel imaging biomarkers that will not only permit assessment of M.tb. burden but also allow monitoring and localization of both adaptive bacterial responses and the hostmicroenvironment (inflammation, hypoxia and early immunity), in the same, live animal, over several timepoints. These tools will be utilized to address fundamental controversies in TB pathogenesis that cannot be tackled using current tools: a) Are host tissue inflammation and hypoxia a sanctuary for "dormant" M.tb.? b) Where do "dormant" M.tb. reside? c) Is innate immunity required for controlling initial M.tb. infection? Knowledge gained from this proposal will provide unique insights for developing better anti-TB drugs/vaccines. By permitting cost-effective, cross-species pre-clinical assessment, these tools will also dramatically reduce the time required for "bench-to-bedside" translation. Finally, since these tools are easily translatable, preclinical validation will lay the groundwork for their future use in humans.

Public Health Relevance

Recognizing that tuberculosis (TB) is still one of the leading causes of human death, the international health-community has set ambitious targets to eliminate TB by 2050;unfortunately this cannot be achieved with current tools and requires the development and use of better anti-TB drugs / vaccines. In this proposal, we will develop novel imaging biomarker tools to address fundamental controversies in TB pathogenesis that cannot be tackled using current tools. Knowledge gained from this proposal will provide unique insights for development of better anti-TB drugs / vaccines;dramatically reduce the time required for bench-to-bedside translation of new drugs / vaccines and lay the groundwork for the future use of these imaging biomarkers for evaluating TB in humans.

Agency
National Institute of Health (NIH)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
4DP2OD006492-02
Application #
8786468
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Basavappa, Ravi
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Ordonez, Alvaro A; Weinstein, Edward A; Bambarger, Lauren E et al. (2016) A Systematic Approach for Developing Bacteria-Specific Imaging Tracers. J Nucl Med :
Ordonez, Alvaro A; Tasneen, Rokeya; Pokkali, Supriya et al. (2016) Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9. Dis Model Mech 9:779-88
Kübler, André; Luna, Brian; Larsson, Christer et al. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 235:431-44
Luna, Brian; Kubler, André; Larsson, Christer et al. (2015) In vivo prediction of tuberculosis-associated cavity formation in rabbits. J Infect Dis 211:481-5
DeMarco, Vincent P; Ordonez, Alvaro A; Klunk, Mariah et al. (2015) Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemother 59:5768-74
Salazar-Austin, Nicole; Ordonez, Alvaro A; Hsu, Alice Jenh et al. (2015) Extensively drug-resistant tuberculosis in a young child after travel to India. Lancet Infect Dis 15:1485-91
Ordonez, Alvaro A; DeMarco, Vincent P; Klunk, Mariah H et al. (2015) Imaging Chronic Tuberculous Lesions Using Sodium [(18)F]Fluoride Positron Emission Tomography in Mice. Mol Imaging Biol 17:609-14
Ordonez, Alvaro A; Pokkali, Supriya; DeMarco, Vincent P et al. (2015) Radioiodinated DPA-713 imaging correlates with bactericidal activity of tuberculosis treatments in mice. Antimicrob Agents Chemother 59:642-9
Xu, Ziyue; Bagci, Ulas; Jonsson, Colleen et al. (2014) Efficient ribcage segmentation from CT scans using shape features. Conf Proc IEEE Eng Med Biol Soc 2014:2899-902
Johnson, Daniel H; Via, Laura E; Kim, Peter et al. (2014) Nuclear imaging: a powerful novel approach for tuberculosis. Nucl Med Biol 41:777-84

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