# Effectors of Brucella intracellular replication

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2021 · $371,887

## Abstract

Project Summary
Intracellular bacterial pathogens cause a large number of diseases of public health importance. Their
intracellular cycle is key to virulence and culminates in the biogenesis of a niche dedicated to their
survival, proliferation or persistence, a feat achieved via their subversion of host cell functions.
Determining the mechanisms used to create these niches is critical to understanding their pathogenesis,
providing broad insights into pathogenic themes shared by microbes. Bacterial subversion of host cell
functions invokes delivery of effector proteins, whose modes of action hold keys to their pathogenic
mechanisms. Bacteria of the genus Brucella, the causative agents of the world-widespread zoonosis
brucellosis, generate a replication-permissive organelle, the Brucella-containing vacuole (rBCV), which is
essential to their pathogenesis and derived from the host endoplasmic reticulum (ER). rBCV biogenesis
requires the Brucella VirB Type IV secretion system (T4SS) and host secretory trafficking, suggesting it
is controlled by T4SS-delivered effector proteins that modulate specific secretory functions. Yet, the
bacterial effectors and host factors of rBCV biogenesis are mostly unknown. We recently discovered
Brucella VirB T4SS effectors (BspA, BspB and BspF) that target the host secretory pathway, contribute
to either rBCV biogenesis or bacterial growth within rBCVs, and interact with various host proteins
functionally associated with either ER-associated degradation (ERAD) or secretory trafficking at the Golgi
apparatus. These findings provide timely opportunities to address outstanding questions about the
molecular mechanisms of rBCV biogenesis. Here we propose to elucidate the mechanisms by which the
newly identified T4SS effector proteins BspA, BspB and BspF modulate distinct host secretory functions
to promote rBCV biogenesis and bacterial proliferation. We will use molecular and cellular approaches
to first dissect the mode of action of BspB in modulating Golgi-associated secretory trafficking via its
interaction with the COG complex, and define how it contributes to rBCV biogenesis. Second, we will
determine whether BspF targeting of optineurin (OPTN)-mediated functions in post-Golgi vesicular
trafficking mediates its role in Brucella intracellular replication. Last, we will examine whether BspA
modulates ER-associated degradation (ERAD) via its targeting of the ERAD E3 ubiquitin ligase MARCH6
to facilitate rBCV biogenesis and Brucella proliferation. The successful completion of this project will
provide the first characterizations of Brucella effectors involved in rBCV biogenesis via targeting of host
secretory functions. By identifying novel host functions involved in the Brucella intracellular cycle, the
proposed research will define new paradigms of pathogenic exploitation of the host secretory pathway
applicable to the many intracellular microbes that target this cellular compartment, therefore having a
broad impact on ...

## Key facts

- **NIH application ID:** 10074517
- **Project number:** 5R01AI129992-05
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** JEAN A CELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,887
- **Award type:** 5
- **Project period:** 2017-01-05 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074517

## Citation

> US National Institutes of Health, RePORTER application 10074517, Effectors of Brucella intracellular replication (5R01AI129992-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10074517. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*