Virulence Mechanisms of Leukotoxin from Aggregatibacter actinomycetemcomitans

Aggregatibacter actinomycetemcomitans is a gram-negative bacterium that is present in the oral cavity of a large proportion of the human population (Zambon et al., 1983; Henderson et al., 2010) The bacterium is acquired through transmission from infected individuals and thought to initially colonize oral mucosa as a facultative intracellular pathogen (Fine et al., 2006). When the bacteria translocate to a site in the subgingival crevices, a persistent colonization may lead to periodontal destruction and development of periodontitis in susceptible individuals (Fig. 1) (Philstrom et al., 2005; Darveau 2010). The prevalence of this bacterium shows a great variation depending on geographic origin, age and life stile of the examined population (Kinane et al., 2008; Habek 2010). A. actinomycetemcomitans is a part of the normal flora in many healthy individuals but it is also a major agent in some aggressive forms of periodontitis (Fine et al., 2006). Periodontitis is a chronic infection characterized by the destruction of tooth-supporting structures (Darveau 2010). The number and composition of bacteria in the subgingival dental plaque, as well as life stile and genetic predisposition are factors that determine the outcome of the disease activity (Philstrom et al., 2005; Darveau 2010). The genetic diversity among different isolates of A. actinomycetemcomitans is great and its ability to express and release virulence factors varies (Henderson et al., 2010). The different adhesins and fimbriae expressed by this bacterium have been shown to be important factors that promote colonization at the various ecological niches of the human oral cavity (Fine et al., 2006). A. actinomyctemcomitans expresses two exotoxins, a cytolethal distending toxin (Cdt) and a leukotoxin. Cdt ́s are expressed by a number of gram-negative bacteria and causes death of the host cells by blocking their proliferation (Belibasakis et al., 2004). The leukotoxin selectively affects human cells of hematopoetic origin by binding to the lymphocyte function associated receptor 1 (LFA-1) and cause disruption of the membrane integrity (Lally et al., 1999). Leukotoxin belongs to the Repeat in Toxin family (RTX) and shares genomic organization and molecular structures with RTX proteins produced by a number of other gram-negative bacteria (Linhortavá et al., 2010). The expression of leukotoxin and Cdt varies among different A. actinomycetemcomitans isolates and high leukotoxin expression has been shown to correlate with disease while the role of Cdt still is more unclear (Henderson et al.,