# The Genetic Basis of Bone Disease in Mycobacterial Infection

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $435,628

## Abstract

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.

## Key facts

- **NIH application ID:** 9990656
- **Project number:** 5R01AI127715-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Sunhee Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,628
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990656

## Citation

> US National Institutes of Health, RePORTER application 9990656, The Genetic Basis of Bone Disease in Mycobacterial Infection (5R01AI127715-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990656. Licensed CC0.

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