# Coxiella secreted proteins mediating inter-organelle membrane contact sites

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $191,875

## Abstract

PROJECT SUMMARY/ABSTRACT
Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever. Inside the host cell,
the bacterium survives in a phagolysosome-like vacuole called the Coxiella Containing Vacuole (CCV). Coxiella
is uniquely sensitive to host cholesterol levels, where elevated cholesterol, especially in the CCV and
endolysosomal system, leads to bacterial death. While Coxiella directly regulates host cholesterol homeostasis
through effector proteins secreted by the Coxiella Type 4B Secretory System (T4BSS), the T4BSS effector
proteins responsible for manipulating host cell cholesterol have not yet been identified. Using a bioinformatic
approach, we identified a new family of Coxiella T4BSS effector proteins which contain a eukaryotic FFAT motif.
In eukaryotic cells, FFAT proteins bind to the VAP protein family on the endoplasmic reticulum (ER) and mediate
membrane contact sites (MCS) between cell organelles and ER. These inter-organelle MCS play a critical role
in regulating lipid homeostasis. The proposed experiments will test our hypothesis that Coxiella FFAT-containing
T4BSS effector proteins mediate MCS between the ER and other host organelles in order to manipulate host
cholesterol metabolism. Aim 1 will establish which members of the Coxiella FFAT protein family bind to VAP
proteins, and determine where these proteins localize in the host cell. Aim 2 will test whether these proteins are
essential for Coxiella infection, as well as whether they function in modulating host cholesterol. Completion of
these studies will not only reveal a new strategy utilized by Coxiella to modulate host lipid metabolism, but
significantly add to our knowledge on how pathogen-secreted proteins manipulate the host cell.

## Key facts

- **NIH application ID:** 10734795
- **Project number:** 5R21AI173990-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** STACEY D GILK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $191,875
- **Award type:** 5
- **Project period:** 2022-11-04 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734795

## Citation

> US National Institutes of Health, RePORTER application 10734795, Coxiella secreted proteins mediating inter-organelle membrane contact sites (5R21AI173990-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10734795. Licensed CC0.

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