Lymphoid Susceptibility to the Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin (Cdt) is Dependent Upon Baseline Levels of the Signaling Lipid, Phosphatidylinositol-3,4,5-Triphosphate
Date of this Version
Molecular Oral Microbiology
The leukotoxin (LtxA) produced by Aggregatibacter actinomycetemcomitans kills host immune cells, allowing the bacterium to establish an ecological niche in the upper aerodigestive tract of its human host. The interaction of LtxA with human immune cells is both complex and multifaceted, involving membrane lipids as well as cell-surface proteins. In the initial encounter with the host cell, LtxA associates with lymphocyte function-associated antigen-1 (LFA-1), a cell surface adhesion glycoprotein. However, we have also demonstrated that the toxin associates strongly with the plasma membrane lipids, specifically cholesterol. This association with cholesterol is regulated by a cholesterol recognition amino acid consensus (CRAC) motif, with a sequence of 334LEEYSKR340, in the N-terminal region of the toxin. Here, we have demonstrated that removal of cholesterol from the plasma membrane or mutation of the LtxA CRAC motif inhibits the activity of the toxin in THP-1 cells. To inhibit LtxA activity, we designed a short peptide corresponding to the CRAC336 motif of LtxA (CRAC336WT). This peptide binds to cholesterol and thereby inhibits the toxicity of LtxA in THP-1 cells. Previously, we showed that this peptide inhibits LtxA toxicity against Jn.9 (Jurkat) cells, indicating that peptides derived from the cholesterol-binding site of LtxA may have a potential clinical applicability in controlling infections of RTX-producing organisms.
This is the pre-peer reviewed version of the following article: [Shenker, B. J., Walker, L. P., Zekavat, A., & Boesze-Battaglia, K. (2016). Lymphoid susceptibility to the Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is dependent upon baseline levels of the signaling lipid, phosphatidylinositol-3,4,5-triphosphate. Molecular Oral Microbiology, 31(1), 33–42. http://doi.org/10.1111/omi.12127], which has been published in final form at http://doi.org/10.1111/omi.12127]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Shenker, B. J., Walker, L. P., Zekavat, A., & Boesze-Battaglia, K. (2016). Lymphoid Susceptibility to the Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin (Cdt) is Dependent Upon Baseline Levels of the Signaling Lipid, Phosphatidylinositol-3,4,5-Triphosphate. Molecular Oral Microbiology, 31 (1), 33-42. http://dx.doi.org/10.1111/omi.12127
Date Posted: 01 March 2022
This document has been peer reviewed.