Grant Abstract: Cytotoxic mechanisms of Aggregatibacter actinomycetemcomitans leukotoxin

Grant Number: 5R00DE022795-04
PI Name: Brown
Project Title: Cytotoxic mechanisms of Aggregatibacter actinomycetemcomitans leukotoxin

Abstract: The Gram negative pathogen, Aggregatibacter actinomycetemcomitans, is the etiologic agent of localized aggressive periodontitis (LAP) and other systemic infections, including infective endocarditis. LAP, which affects medically-underserved children in both the United States and throughout the world, is characterized by a breakdown of the periodontal ligament and alveolar bone structure that holds the teeth in place. Without intervention, loss of teeth occurs, causing both a cosmetic deformity and a functional defect. The manner in which A. actinomycetemcomitans causes LAP is not known; however, it is known that it produces several putative virulence factors, including a leukotoxin (LtxA), a member of the repeats-in-toxin (RTX) family. Based on experimental and clinical data, LtxA is believed to be a primary virulence factor for the bacterium. Thus, preventing or interfering with LtxA activity may be one option for treatment of disease. The toxin kills human and primate white blood cells and likely plays a role in A. actinomycetemcomitans evasion of the immune response during infection.
We have demonstrated that in its initial response with the host cell, LtxA interacts strongly with the membrane lipids, and changes in the membrane structure can greatly alter the ability of the toxin to kill target cells. In the funded project, we are studying specific molecules that can inhibit the ability of LtxA to interact with the target cell membrane as a means of preventing disease. In this supplement, we propose to investigate the specific use of catechins to inhibit LtxA activity to prevent disease. Catechins have demonstrated membrane activity and antibacterial properties; our goal in this project is to link those findings to specifically show the mechanisms by which catechins alter toxin activity and the role this plays in disease reduction.

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