Mycobacterium tuberculosis infections kill more than one million people annually. Although tuberculosis generally remains confined to the lung, mycobacteria also are able to disseminate to other tissues including bone. The interplay of bacterial and host factors that contribute to infection site, particularly bone infection, is incompletely understood. We have identified an outbreak strain that we find clinically to present with high rates of extrapulmonary dissemination and an unprecedented rate of tuberculous bone disease. We are analyzing this unique isolate of Mycobacterium tuberculosis to determine what strain- specific factors may be responsible for the proclivity to cause bone infection. We have sequenced and assembled the NCG genome and find that is a member of an ancient clade. We hypothesize that unique genetic variants of the NCG strain confer bone tropism. In order to understand the interactions of virulent mycobacteria with bone, we will 1) develop a zebrafish model to directly examine dissemination and bone disease during mycobacterial infection. Bone tissue is continuously remodeled by bone-forming osteoblasts and bone-resorbing osteoclasts; an imbalance in either or both processes can result in bone disease. Using a zebrafish model, we will observe in whole live animals in real time the impact of mycobacterial infection on bone tissue remodeling. 2) We will identify unique variants in the outbreak strain genome and use the zebrafish platform to assess their functional relevance in bone disease. 3) In a parallel approach, we will use mouse models to interrogate and validate specific genetic variants using aerosol infections with the outbreak strain. These studies will provide insights into the functiona significance of specific genetic variants during infection with an outbreak strain as well as the basis of mycobacterial dissemination and bone disease.

Public Health Relevance

This project will investigate why some tuberculosis infections remain in the lung while others disseminate to other parts of the body. It will focus on one tuberculosis outbreak strain with a high rate of dissemination to bone. Using animal models, the project aims to understand how infecting bacteria escape the initial site of infection and subsequently damage bone tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI111067-01A1
Application #
8824043
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lacourciere, Karen A
Project Start
2014-12-01
Project End
2016-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Cronan, Mark R; Beerman, Rebecca W; Rosenberg, Allison F et al. (2016) Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection. Immunity 45:861-876
Saelens, Joseph W; Lau-Bonilla, Dalia; Moller, Anneliese et al. (2015) Whole genome sequencing identifies circulating Beijing-lineage Mycobacterium tuberculosis strains in Guatemala and an associated urban outbreak. Tuberculosis (Edinb) 95:810-816
Cronan, Mark R; Rosenberg, Allison F; Oehlers, Stefan H et al. (2015) CLARITY and PACT-based imaging of adult zebrafish and mouse for whole-animal analysis of infections. Dis Model Mech 8:1643-50