# Regulation of LPS structure and function in Porphyromonas gingivalis

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2024 · $205,406

## Abstract

Project Summary/Abstract 
Periodontitis is a highly prevalent infectious, inflammatory disease of the tissues supporting the teeth that can 
lead to tissue destruction, formation of a deep periodontal pocket, alveolar bone resorption, and tooth loss. 
Etiological models suggest that periodontitis is driven by a synergistic community of virulent bacteria that trigger 
host inflammatory responses in the gingival tissues resulting in disease progression. Among recognized 
pathogens, the Gram-negative anaerobe Porphyromonas gingivalis (Pg) has been strongly implicated in 
periodontitis. Lipopolysaccharide (LPS) macromolecules produced by Pg strains have been repeatedly shown 
to stimulate pro-inflammatory innate immune responses. Intriguingly, Pg strains can diversify the structure of 
LPS in response to biologically relevant stimuli to temporarily disguise themselves, evade the immune system, 
protect from stresses, and promote survival. Accordingly, at least four LPS variants have been identified in Pg 
strains that may act as agonists or antagonists in the interaction with the innate immune system. Agonistic LPS 
plays prominent roles in the pathological outcome of infection by being involved in the activation of TLR signaling 
pathways leading to production of proinflammatory cytokines, tissue destruction, and bone resorption. However, 
we do not yet know the mechanisms of the regulation of LPS heterogeneity and its biological importance during 
pathogenesis. We discovered that Pg strains possess a c-di-AMP signaling mechanism in which the c-di-AMP 
synthase PGN_0523 (dacpg) and the c-di-AMP phosphodiesterase PGN_0521 (pdepg) control the essential 
turnover of c-di-AMP, and consequently LPS heterogeneity and virulence potential. This study will investigate 
how c-di-AMP turnover regulates the heterogeneity and immunomodulatory properties of Pg LPS using in vitro 
and in vivo models. To this end, two independent but related specific aims are proposed: Specific Aim 1: To 
understand how c-di-AMP-controls heterogeneity of LPS in Pg. Specific Aim 2: To understand the impact of c- 
di-AMP-dependent variation of LPS on the innate immune response. Upon completion of the proposed studies, 
we will learn how c-di-AMP signaling controls Pg LPS heterogeneity and determines the innate immune 
responses. Since c-di-AMP signaling does not exist in humans, it is a potential novel druggable target. Our 
findings will inform the discovery of potent antagonistic LPS isoforms as a foundation for development of anti- 
inflammatory therapeutics.

## Key facts

- **NIH application ID:** 10795832
- **Project number:** 5P20GM125504-07
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Fata Moradali
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $205,406
- **Award type:** 5
- **Project period:** 2018-03-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795832

## Citation

> US National Institutes of Health, RePORTER application 10795832, Regulation of LPS structure and function in Porphyromonas gingivalis (5P20GM125504-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10795832. Licensed CC0.

---

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