Mycobacterium tuberculosis (Mtb) infections kill approximately 1.5 million people annually. Although tuberculosis generally remains confined to the lung, pathogenic mycobacteria also are able to disseminate to other tissues. The interplay of bacterial and host factors that contribute to dissemination is incompletely understood. We identified an outbreak strain that presents with high rates of extrapulmonary dissemination and an extremely high rate of tuberculous bone disease. We have sequenced and assembled the NCG genome and find that is a member of an ancient Mtb lineage. We have identified the Type VII secretion system substrate EsxM as intact in the outbreak strain but truncated in all modern Mtb strains and hypothesize that the ancient variant is an important contributor to bone dissemination. We have developed a zebrafish model to directly examine dissemination and bone disease during mycobacterial infection with Mycobacterium marinum. Using this model we can perform live visualization of osteoblast and osteoclast dynamics. We have found that the full-length versions of EsxM found in M. marinum and ancient lineages of Mtb promote dissemination to bone and are sufficient to modulate macrophage motility. We will 1) interrogate the function of EsxM in modulating the behavior of infected macrophages; 2) identify mechansisms by which EsxM interacts with specific host proteins in macrophages 3) translate these findings in mouse models of dissemination and bone disease. These studies will provide insights into the genetic basis of mycobacterial dissemination and bone disease, a fundamentally important question in our understanding of tuberculosis and other infectious diseases.

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
Research Project (R01)
Project #
5R01AI127715-03
Application #
9730388
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Eichelberg, Katrin
Project Start
2017-08-15
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
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; 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
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