# ROLE OF ESXG-ESXH IN MYCOBACTERIUM TUBERCULOSIS PATHOGENESIS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $426,149

## Abstract

PROJECT SUMMARY
Mycobacterium tuberculosis (Mtb) kills more people yearly than any other infection. Mtb is successful
because it impairs key functions of macrophages and dendritic cells. Mtb survives in macrophages by
preventing the normal maturation of the phagosome, creating a replicative niche that resembles an early
endosome. By impairing MHC class II (MHCII) antigen presentation, Mtb undermines CD4+ T cell recognition
of infected macrophages. A detailed understanding of how Mtb undermines these processes is lacking. We
found that the Mtb secreted proteins, EsxG and EsxH, play a critical role in both processes. EsxG and EsxH
are secreted as a heterodimer (EsxG-EsxH). We identified a host target of EsxG-EsxH: hepatocyte growth
factor-regulated tyrosine kinase substrate (HGS/HRS). HRS is a component of the endosomal sorting
complex required for transport (ESCRT) machinery. ESCRT plays a well-described role in trafficking cell
surface receptors to the lysosome for degradation. We also found that ESCRT is required for phagosome
maturation and optimal antigen presentation. Therefore, by inhibiting ESCRT, EsxG-EsxH can promote Mtb
survival in multiple ways. Now, our new preliminary data suggest that EsxG-EsxH also targets
oculocerebrorenal syndrome of Lowe (OCRL). OCRL is an inositol 5-phosphatase with substrate specificity
for phosphatidlylinositol-4,5-bisphosphate. Like HRS, OCRL is involved in endosome and phagosome
function. The central hypothesis of this grant is that EsxG-EsxH impairs the function of both OCRL and HRS,
thereby blocking phagosome maturation, inhibiting antigen presentation, and promoting Mtb virulence. We
propose that EsxG-EsxH impairs recruitment of both OCRL and HRS to mycobacterial phagosomes. In the
case of OCRL, we hypothesize that EsxG blocks the ability of OCRL to interact with its endosomal binding
partner. In the case of HRS, we hypothesize that EsxG-EsxH promote HRS ubiquitination, which locks the
molecule in an inactive form. We will determine whether EsxG-EsxH inhibits OCRL, define how it impairs
HRS, and test the contribution of both EsxG-EsxH targets to infection in vivo. Our previous work on this
project makes us uniquely qualified to carry out these studies. Our findings will provide further important
mechanistic insight into Mtb's virulence strategies. We will also elucidate the importance of OCRL and
ESCRT in basic macrophage biology. Revealing the fundamental basis by which Mtb sabotages host cellular
functions will lead to better therapies and vaccines for Mtb.

## Key facts

- **NIH application ID:** 10083166
- **Project number:** 5R01AI087682-09
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JENNIFER A PHILIPS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,149
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083166

## Citation

> US National Institutes of Health, RePORTER application 10083166, ROLE OF ESXG-ESXH IN MYCOBACTERIUM TUBERCULOSIS PATHOGENESIS (5R01AI087682-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083166. Licensed CC0.

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