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Toxins 2018, 10(10), 414; https://doi.org/10.3390/toxins10100414

Aggregatibacter actinomycetemcomitans Leukotoxin Is Delivered to Host Cells in an LFA-1-Indepdendent Manner When Associated with Outer Membrane Vesicles

1
Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA
2
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA
3
Department of Oral Biology, Rutgers University School of Dental Medicine, Newark, NJ 07101, USA
*
Author to whom correspondence should be addressed.
Received: 24 August 2018 / Revised: 8 October 2018 / Accepted: 10 October 2018 / Published: 13 October 2018
(This article belongs to the Special Issue Leukotoxins)
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Abstract

The Gram-negative bacterium, Aggregatibacter actinomycetemcomitans, has been associated with localized aggressive periodontitis (LAP). In particular, highly leukotoxic strains of A. actinomycetemcomitans have been more closely associated with this disease, suggesting that LtxA is a key virulence factor for A. actinomycetemcomitans. LtxA is secreted across both the inner and outer membranes via the Type I secretion system, but has also been found to be enriched within outer membrane vesicles (OMVs), derived from the bacterial outer membrane. We have characterized the association of LtxA with OMVs produced by the highly leukotoxic strain, JP2, and investigated the interaction of these OMVs with host cells to understand how LtxA is delivered to host cells in this OMV-associated form. Our results demonstrated that a significant fraction of the secreted LtxA exists in an OMV-associated form. Furthermore, we have discovered that in this OMV-associated form, the toxin is trafficked to host cells by a cholesterol- and receptor-independent mechanism in contrast to the mechanism by which free LtxA is delivered. Because OMV-associated toxin is trafficked to host cells in an entirely different manner than free toxin, this study highlights the importance of studying both free and OMV-associated forms of LtxA to understand A. actinomycetemcomitans virulence. View Full-Text
Keywords: Aggregatibacter actinomycetemcomitans; outer membrane vesicles; leukotoxin; cholesterol; lymphocyte function-associated antigen-1 (LFA-1); RTX toxin Aggregatibacter actinomycetemcomitans; outer membrane vesicles; leukotoxin; cholesterol; lymphocyte function-associated antigen-1 (LFA-1); RTX toxin
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Nice, J.B.; Balashova, N.V.; Kachlany, S.C.; Koufos, E.; Krueger, E.; Lally, E.T.; Brown, A.C. Aggregatibacter actinomycetemcomitans Leukotoxin Is Delivered to Host Cells in an LFA-1-Indepdendent Manner When Associated with Outer Membrane Vesicles. Toxins 2018, 10, 414.

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