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Human CD18 Is the Functional Receptor for Aggregatibacter actinomycetemcomitans Leukotoxin

T. Dileepan,^1, S. C. Kachlany,² N. V. Balashova,² J. Patel,² and S. K. Maheswaran^1*

Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota 55108,¹ Department of Oral Biology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103²

Received 26 February 2007/ Returned for modification 16 April 2007/ Accepted 9 July 2007

Aggregatibacter (Actinobacillus) actinomycetemcomitans is the causative organism of localized aggressive periodontitis, a rapidly progressing degenerative disease of the gingival and periodontal ligaments, and is also implicated in causing subacute infective endocarditis in humans. The bacterium produces a variety of virulence factors, including an exotoxic leukotoxin (LtxA) that is a member of the repeats-in-toxin (RTX) family of bacterial cytolysins. LtxA exhibits a unique specificity to macrophages and polymorphonuclear cells of humans and other primates. Human lymphocyte function-associated antigen 1 (LFA-1) has been implicated as the putative receptor for LtxA. Human LFA-1 comprises the CD11a and CD18 subunits. It is not clear, however, which of its subunits serves as the functional receptor that confers species-specific susceptibility to LtxA. Here we demonstrate that the human CD18 is the receptor for LtxA based on experiments performed with chimeric ß2-integrins recombinantly expressed in a cell line that is resistant to LtxA effects. In addition, we show that the cysteine-rich tandem repeats encompassing integrin-epidermal growth factor-like domains 2, 3, and 4 of the extracellular region of human CD18 are critical for conferring susceptibility to LtxA-induced biological effects.

Published ahead of print on 16 July 2007.

Editor: A. Camilli

Present address: Department of Microbiology, Medical School, University of Minnesota, 1460 Mayo, 420 Delaware Street NE, Minneapolis, MN 55455.