# Two-component signaling systems of Treponema denticola

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $354,143

## Abstract

PROJECT SUMMARY
Periodontitis is one of the most common human health conditions and is a chronic inflammatory disease affecting
the tooth-supporting structures resulting from the actions of polymicrobial communities of organisms that induce
destructive immune responses. Progression of periodontitis is associated with a microbial population shift and
synergistic interactions between pathobionts such as Porphyromonas gingivalis and Treponema denticola. T.
denticola emerges as one of the most abundant bacteria in diseased periodontal sites and is predictive of the
severity and progression of periodontitis. The mechanisms that allow T. denticola to thrive in the diseased
periodontium remain poorly defined. Two-component signal (TCS) transduction systems are ubiquitous sensory
transduction systems in bacteria that often sense environmental stimuli to mediate cellular responses via genetic
regulation. Our scientific premise is that TCSs allow T. denticola to sense and respond to changing periodontal
environments, promoting persistence, interactions with other oral bacteria, and pathogenicity. We have initiated
the characterization of the AtcS/AtcR and Hpk2/Rrp2 TCS of T. denticola, which represents half of the TCS
encoded in the genome. We have characterized the AtcR binding motif and identified genes that contain the
AtcR binding motif within their promoter. Interestingly, the promoter regulating the expression of the Hpk2/Rrp2
TCS is bound by AtcR. Yet, AtcR-mediated regulation of gene expression and the impact on T. denticola cellular
processes are untested. We have observed that Hpk2 kinase activity is regulated by oxygen. However, the role
of Rrp2 as a transcription factor and its regulon remains unstudied. Our ongoing studies indicate that both AtcR
and Rrp2 may co-regulate the expression of genes with the alternative sigma factor, s54. However, no study has
ever explored the role of s54 in T. denticola. The published literature supports our preliminary data suggesting
that AtcR likely contributes to community interactions with P. gingivalis, and both AtcR and Rrp2 likely impact the
fitness and virulence of T. denticola. Here, we propose three complementary Specific Aims that will fill these gaps
in knowledge. Aim 1 will determine how phosphorylation of AtcR impacts DNA binding kinetic, affinity, and
stoichiometry, while knockout of atcR in T. denticola will characterize the role of AtcR in gene regulation and
physiology. Aim 2 will define the Rrp2 and s54 binding sites, demonstrate Rrp2 interacts with s54 to regulate gene
expression and determine if Rrp2-mediated regulation responds to changes in environmental oxygen. Aim 3 will
determine if AtcR and Rrp2 contribute to T. denticola colonization of the gingiva, induction of inflammatory
markers, and alveolar bone loss in murine models of periodontitis. We will then determine if AtcR contributes to
synergistic growth and pathogenicity with P. gingivalis. Completing this study will define half of t...

## Key facts

- **NIH application ID:** 10858774
- **Project number:** 1R01DE033722-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Daniel Patrick Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,143
- **Award type:** 1
- **Project period:** 2024-05-02 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10858774

## Citation

> US National Institutes of Health, RePORTER application 10858774, Two-component signaling systems of Treponema denticola (1R01DE033722-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10858774. Licensed CC0.

---

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