# CsrA mediated regulation of a virulence switch in Acinetobacter baumannii

> **NIH NIH R21** · EMORY UNIVERSITY · 2024 · $160,250

## Abstract

The Gram-negative bacterium Acinetobacter baumannii is a leading cause of
nosocomial infections in humans. The emergence of A. baumannii strains resistant to
most, and in some cases, all available antibiotics has made the treatment of these
infections exceedingly difficult. This underlies the importance of finding new ways to
combat these infections. Our work has demonstrated that A. baumannii can rapidly
switch between virulent (VIR-O) and avirulent (AV-T) subpopulations. This switch is
controlled, in part, by the stochastic activation of a family of TetR-type transcriptional
regulators (TTTRs). Remarkably, these TTTRs can be activated alone or in different
combinations, representing a new mechanism for the generation of phenotypic
heterogeneity in bacteria. Expression of the TTTRs is primarily controlled at the level of
Rho-dependent transcriptional termination within the mRNA leader regions of each
TTTR. In VIR-O cells the level of termination is high and the TTTRs are OFF. In AV-T
cells, termination is blocked by an unknown mechanism and the TTTRs are expressed.
The goals of this proposal are to understand the role of a regulatory cascade beginning
with the GacSA two-component system. We hypothesize that GacA exists in a bistable
ON state in VIR-O cells and an OFF state in AV-T cells. In the ON state, a set of GacA
regulated sRNAs are expressed which inhibit the CsrA protein. In AV-T cells, GacA is
OFF and CsrA is active, and we hypothesize CsrA can then block Rho-dependent
termination in the TTTR leader regions. This switch represents a possible Achilles-heel
for A. baumannii pathogenesis and an increased understanding of the mechanisms that
regulate the switch may lead to interventions that drive virulent cells to the avirulent
state and cripple the ability to cause disease.

## Key facts

- **NIH application ID:** 10989123
- **Project number:** 1R21AI180913-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Philip N. Rather
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $160,250
- **Award type:** 1
- **Project period:** 2024-06-07 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989123

## Citation

> US National Institutes of Health, RePORTER application 10989123, CsrA mediated regulation of a virulence switch in Acinetobacter baumannii (1R21AI180913-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10989123. Licensed CC0.

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