# A. Actinomycetemcomitans Cdt Induces Pro-Inflammatory Innate Immune Responses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $517,486

## Abstract

Periodontal disease is a chronic inflammatory disorder driven by polymicrobial infection. The pathogenesis
of this disorder involves activation, and possibly perturbation, of both innate and adaptive immune responses. Over
the course of our investigation we have demonstrated that Aggregatibacter actinomycetemcomitans (Aa), a
putative pathogen implicated in the pathogenesis of localized aggressive periodontitis (LAP), produces an
immunotoxin, the cytolethal distending toxin (Cdt). Cdt is a heterotrimeric holotoxin which functions as an AB2
toxin: the cell binding (B) units are comprised of the CdtA and CdtC subunits and the active (A) subunit, CdtB.
We have demonstrated that CdtB functions as a 5'-phosphatidylinositol (PI) triphosphate phosphatase as it
degrades the PI-3K signaling lipid, PI-3,4,5-triphosphate (PIP3) to PI-3,4P2; this action leads to blockade of the
signaling pathway. Blockade of PI-3K signaling in human macrophages leads to a pro-inflammatory cytokine
response involving both canonical and noncanonical inflammasome activation. Cdt also induces production of
inflammatory mediators derived from arachidonic acid including PGE2 and thromboxanes. Most recently, we have
observed phagocytic defects in Cdt-treated macrophages consistent with altered phago-lysosome maturation. We
propose that Cdt perturbs macrophage function thereby contributing to both inflammation and sustained infection.
 Our overarching hypothesis is that the Aa Cdt contributes to altered local host defense which facilitate
Aa survival and enables other microbes to evade host defense. The goal of our study is to extend our investigation
and advance our knowledge of the molecular events that link PI-3K signaling blockade to downstream pro-
inflammatory responses and altered vesicular trafficking and fusion. Specifically, we propose that CdtB induces
GSK3â-dependent HSP90 activation and further that HSP90, via its effects on NLRP3, Cox-2 and possibly ESCRT
proteins is a critical intermediary in events leading to release of mature cytokines and eicosanoids (specific aim
1). We plan to advance our understanding of the role that Cdt plays activating the noncanonical inflammasome
which involve gasdermin D (GSDMD) pore formation and pyroptosis. Our focus will be to determine how CdtB
activates caspase-4 and contributes to GSDMD pore formation; the latter studies will focus on PI-3,4P2 and pore
repair via the ESCRT system (specific aim2). In specific aim 3 we will focus on perturbation of vesicular transport
and phago-lysosome formation. We propose that altered PI distribution due in part to CdtB-mediated production
of PI3,4P2 facilitates CdtB retrograde transport and modulates the formation of phago-lysosomes. The long-term
goals of our study are to translate our understanding of the molecular events that govern Cdt toxicity and, in turn,
the pathogenicity of Cdt-producing organisms. These studies are of particular significance as Cdt is produced not
only by Aa but many other...

## Key facts

- **NIH application ID:** 10438935
- **Project number:** 5R01DE023071-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kathleen Boesze-Battaglia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $517,486
- **Award type:** 5
- **Project period:** 2013-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438935

## Citation

> US National Institutes of Health, RePORTER application 10438935, A. Actinomycetemcomitans Cdt Induces Pro-Inflammatory Innate Immune Responses (5R01DE023071-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438935. Licensed CC0.

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