Abstract
Aggregatibacter actinomycetemcomitans is an oral pathogen and etiologic agent of localized aggressive periodontitis. The bacterium is also a cardiovascular pathogen causing infective endocarditis. A. actinomycetemcomitans produces leukotoxin (LtxA), an important virulence factor that targets white blood cells (WBCs) and plays a role in immune evasion during disease. The functional receptor for LtxA on WBCs is leukocyte function antigen-1 (LFA-1), a β-2 integrin that is modified with N-linked carbohydrates. Interaction between toxin and receptor leads to cell death. We recently discovered that LtxA can also lyse red blood cells (RBCs) and hemolysis may be important for pathogenesis of A. actinomycetemcomitans. In this study, we further investigated how LtxA might recognize and lyse RBCs. We found that, in contrast to a related toxin, E. coli α-hemolysin, LtxA does not recognize glycophorin on RBCs. However, gangliosides were able to completely block LtxA-mediated hemolysis. Furthermore, LtxA did not show a preference for any individual ganglioside. LtxA also bound to ganglioside-rich C6 rat glioma cells, but did not kill them. Interaction between LtxA and C6 cells could be blocked by gangliosides with no apparent specificity. Gangliosides were only partially effective at preventing LtxA-mediated cytotoxicity of WBCs, and the effect was only observed when a high ratio of ganglioside:LtxA was used over a short incubation period. Based on the results presented here, we suggest that because of the similarity between N-linked sugars on LFA-1 and the structures of gangliosides, LtxA may have acquired the ability to lyse RBCs.
Highlights
Aggregatibacter actinomycetemcomitans is a gram negative oral bacterium that can cause localized aggressive periodontitis in adolescents (LAP) [1,2,3]
We discovered that LtxA could lyse red blood cells (RBCs) from a variety of species including human, sheep, and horse [20]
It was previously reported that E. coli -hemolysin can use glycophorin, a sialoglycoprotein, on the surface of RBCs, as a receptor [23]
Summary
Aggregatibacter actinomycetemcomitans is a gram negative oral bacterium that can cause localized aggressive periodontitis in adolescents (LAP) [1,2,3]. The bacterium is part of the normal oral flora in many healthy individuals [4,5]. The disease occurs predominantly in African Americans and approximately 70,000 adolescents develop the disease in the U.S per year [6]. LAP is a destructive form of periodontitis that affects the central incisors and first molars, and LAP results in the rapid loss of bone and periodontal ligament surrounding the teeth. In addition to being an important oral pathogen, A. actinomycetemcomitans is part of the HACEK group of bacteria (Haemophilus spp., A. actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) implicated in infective endocarditis (IE) [7,8] and A. actinomycetemcomitans is reported to be the HACEK organism involved most often in IE [9]
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