# The Bacterial Genetic Basis of Bone Disease and Dissemination in Mycobacterial Infection: Roles of ESX-5 Secreted WXG Effectors

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $536,328

## Abstract

Mycobacterium tuberculosis (Mtb) remains a leading cause of infectious death
worldwide. Although tuberculosis generally remains confined to the lung, pathogenic
mycobacteria also can disseminate to other tissues, resulting in some of the most
dangerous manifestations of the infection. The interplay of bacterial and host factors that
contribute to dissemination is incompletely understood. Beginning with an outbreak
strain presenting with high rates of extrapulmonary dissemination and an extremely high
rate of tuberculous bone disease, we identified a full-length vavriant of the Type VII
secretion system substrate EsxM as an important component of the clinical phenotype.
EsxM was intact in the outbreak strain and so-called “ancestral lineages” but truncated in
modern Mtb strains. The active version of EsxM modulates the motility of infected
macrophages leading to dissemination, but has been compromised in “modern-lineage”
Mtb strains. The work proposed here will 1) interrogate the mechanisms by which the
bacterial secreted effector EsxM modulates the behavior of infected macrophages; 2)
identify how EsxM and its closely related paralogs are regulated in the bacteria during
infection, including investigating non-redundant roles for the closely-related paralogs;
and 3) translate these findings into murine and zebrafish models of dissemination and
bone disease. These studies will provide insights into the bacterial genetic regulators of
dissemination of infection, a fundamentally important question in our understanding of
tuberculosis and other infectious diseases.

## Key facts

- **NIH application ID:** 10798665
- **Project number:** 2R01AI127715-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Clare Margaret Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,328
- **Award type:** 2
- **Project period:** 2017-08-15 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798665

## Citation

> US National Institutes of Health, RePORTER application 10798665, The Bacterial Genetic Basis of Bone Disease and Dissemination in Mycobacterial Infection: Roles of ESX-5 Secreted WXG Effectors (2R01AI127715-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10798665. Licensed CC0.

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