Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Abstract

Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis, as well as other systemic diseases. This organism produces a number of virulence factors, all of which provide some advantage to the bacterium. Several studies have demonstrated that clinical isolates from diseased patients, particularly those of African descent, frequently belong to specific clones of A. actinomycetemcomitans that produce significantly higher amounts of a protein exotoxin belonging to the repeats-in-toxin (RTX) family, leukotoxin (LtxA), whereas isolates from healthy patients harbor minimally leukotoxic strains. This finding suggests that LtxA might play a key role in A. actinomycetemcomitans pathogenicity. Because of this correlation, much work over the past 30 years has been focused on understanding the mechanisms by which LtxA interacts with and kills host cells.In this article, we review those findings, highlight the remaining open questions, and demonstrate how knowledge of these mechanisms, particularly the toxin's interactions with lymphocyte function-associated antigen-1 (LFA-1) and cholesterol, enables the design of targeted anti-LtxA strategies to prevent/treat disease. K E Y W O R D SAggregatibacter actinomycetemcomitans, leukotoxin, LFA-1, repeats-in-toxin

Prevalence of JP2 and Non-JP2 Genotypes of Aggregatibacter actinomycetemcomitans and Oral Hygiene Practice of Kenyan Adolescents in Maasai Mara

“…We then might be able to recommend or even develop new oral hygiene tools and preventive strategies for the future that are acceptable to the focus population. For example, plant materials may contain beneficial plant extracts that exert an anti-leukotoxic potential [ 32 , 33 , 34 , 35 ]. Recently, proanthocyanidins and epigallocatechin gallate of plant origin have been found to neutralize the effect of the A. actinomycetemcomitans leukotoxin [ 35 , 36 , 37 ].…”

Expression of virulence factors under different environmental conditions in Aggregatibacter actinomycetemcomitans

“…1,2 Among periodontopathogenic bacteria, the characteristic feature of A. actinomycetemcomitans is that this bacterium produces two toxins, namely, leukotoxin and cytolethal distending toxin (CDT). [1][2][3][4][5] Leukotoxin is a member of the repeats-in-toxin family of cytolysins. 1 Four genes, namely, lktCABD (also known as ltxCABD), constitute an operon for this toxin.…”

“…2 Leukotoxin acts on leukocytes, including polymorphonuclear leukocytes, lymphocytes, and monocytes/macrophages. 1,4,5 A region of the toxin containing a series of 14 tandemly repeated amino acids is responsible for the binding to lymphocyte function-associated antigen 1 causing the insertion of this toxin into the cell membrane. CDT is another important toxin in A. actinomycetemcomitans.…”

“…Aggregatibacter actinomycetemcomitans is a facultative anaerobic Gram‐negative bacterium that is associated with the onset of periodontitis, especially aggressive periodontitis 1,2 . Among periodontopathogenic bacteria, the characteristic feature of A. actinomycetemcomitans is that this bacterium produces two toxins, namely, leukotoxin and cytolethal distending toxin (CDT) 1–5 . Leukotoxin is a member of the repeats‐in‐toxin family of cytolysins 1 .…”

“…The gene lktA encodes the structural protein of the toxin, while others are associated with the posttranslational acylation of the toxin ( lktC ) and the transport of the toxin to the outer membrane ( lktB and ltktD ) 2 . Leukotoxin acts on leukocytes, including polymorphonuclear leukocytes, lymphocytes, and monocytes/macrophages 1,4,5 . A region of the toxin containing a series of 14 tandemly repeated amino acids is responsible for the binding to lymphocyte function‐associated antigen 1 causing the insertion of this toxin into the cell membrane.…”