# The regulatory role of an RNA binding protein in two-component signaling and its impact on cellular physiology and anthrax pathogenesis

> **NIH NIH F32** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $2,500

## Abstract

SUMMARY
 Antibiotic resistance among bacterial pathogens is spreading rapidly around the world. Therefore, it is
urgent to develop strategies to discover novel antimicrobial agents. Two component system (TCSs) are ideal
targets for developing novel antimicrobial treatments for at least two reasons: (i) they are often essential for
bacterial growth within the host; (ii) they are common in bacteria but evidently absent in human and animals.
TCSs have been studied for decades and the molecular basis of signal transduction is well known, however,
important questions remain regarding regulation of these signaling systems. In this application, I will use the
intracellular human pathogen Bacillus anthracis as a model organism and investigate the regulatory mechanism
of the HitRS signaling system. This TCS senses the phagocyte cell environment and provides a direct fitness
advantage during the interactions with the host immune cells. Furthermore, the HitRS system is activated by a
variety of molecular distinct cell envelope stressors, suggesting that additional cellular factors must be required
for activation of this system. Indeed, using an unbiased genetic selection strategy, we identified an RNA binding
protein KreA (ComK repressor in B. anthracis) that plays a critical role in HitRS activation through modulating
mRNA stability of the TCS transcripts. In addition, our preliminary data demonstrate that KreA functions as an
RNA binding protein (RBP) and plays an important post-transcriptional regulatory role in HitRS signaling.
 The importance of bacterial post-transcriptional control has been increasingly appreciated in recent years
although the mechanisms of these regulatory networks are poorly understood in bacteria. Based on our
preliminary data, we propose a model that the newly identified RBP KreA binds mRNA at specific target sites,
impacts expression of functionally coordinated sets of mRNAs, interacts with other RBPs dynamically to facilitate
mRNA decay, and promotes bacterial survival within the mammalian hosts. In this application, we will combine
a number of strategies including biochemical analysis, genetics, transcriptomics, proteomics, live cell imaging,
and mouse infection models to (i) define the direct RNA targets and binding preference of KreA, (ii) elucidate the
underlying mechanism of KreA in regulating HitRS signaling, (iii) determine the functional ramifications of KreA-
modulated RNA stability on bacterial physiology, and (iv) dissect the contribution of HitRS signal transduction
and KreA-mediated RNA regulation during phagocytosis and anthrax pathogenesis. Moreover, the results
obtained from this study will provide new insights into TCS regulation, expand our knowledge of bacterial post-
transcriptional regulatory networks, and lay the groundwork for developing novel antimicrobial therapeutics.

## Key facts

- **NIH application ID:** 10436636
- **Project number:** 3F32AI161860-01S1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Hualiang Pi
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436636

## Citation

> US National Institutes of Health, RePORTER application 10436636, The regulatory role of an RNA binding protein in two-component signaling and its impact on cellular physiology and anthrax pathogenesis (3F32AI161860-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436636. Licensed CC0.

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