# The role of pH and iron in co-regulating replication and expression of virulence factors in Coxiella burnetii

> **NIH NIH F31** · WASHINGTON STATE UNIVERSITY · 2020 · $38,594

## Abstract

7. Project Summary/Abstract
Coxiella burnetii, the causative agent of Query (Q) fever in humans and coxiellosis in other species is a highly
infectious obligate intracellular bacterium. In humans, this disease is largely self-limiting, presenting as an
acute febrile disease; however, the pathogen is capable of causing both hepatitis and potentially life-
threatening endocarditis. C. burnetii is capable of infecting a broad range of eukaryotic cell types within which
the bacterium replicates exclusively in a host-derived compartment referred to as the Coxiella Containing
Vacuole (CCV). CCV biogenesis is dependent on C. burnetii secretion of Type IV secretion system (T4SS)
effector molecules and in their absence the bacterium is unable to replicate intracellularly and/or exhibit
virulence. Studies on the physicochemical requirements of C. burnetii have established that the moderately
acidic pH of the CCV, a phagolysosome-like vacuole, dictates C. burnetii nutrient transport, protein synthesis
and replication. Additionally, C. burnetii exhibits tropism for tissues directly involved in iron storage and
recycling (e.g., the liver and splenic red pulp). High iron loads in the liver and splenic red pulp, and known
uptake of extracellular material into the CCV lumen by fluid phase endocytosis, is consistent with uptake of
iron-containing molecules (e.g., transferrin) into the CCV. Cultured host cells infected with C. burnetii have
been shown to increase expression of transferrin receptors, suggesting a demand for iron, a micronutrient
previously reported to have a limited role in C. burnetii pathogenesis. While genome sequence analysis
suggests C. burnetii has a limited capacity to acquire iron via siderophores or uptake systems for iron-
containing molecules, the C. burnetii genome does encode the ferrous iron uptake transporter FeoAB
suggesting that molecular iron is the natural iron source for C. burnetii. Additionally, the C. burnetii genome
encodes the transcriptional regulator stringent starvation protein A (SspA) that in Escherichia coli has been
shown to positively regulate genes involved in acid tolerance. Since replication is essential for virulence, and
replication is dependent on both moderately acidic pH and iron, we hypothesize that pathogen replication is
triggered by simultaneous sensing of niche-specific variables (i.e., acidic pH and iron) that co-regulate
expression of virulence factors required for CCV biogenesis and pathogen growth.

## Key facts

- **NIH application ID:** 9911243
- **Project number:** 1F31AI150167-01
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Savannah Elizabeth Sanchez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,594
- **Award type:** 1
- **Project period:** 2020-08-16 → 2022-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911243

## Citation

> US National Institutes of Health, RePORTER application 9911243, The role of pH and iron in co-regulating replication and expression of virulence factors in Coxiella burnetii (1F31AI150167-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9911243. Licensed CC0.

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