Actinobacillus actinomycetemcomitans is a bacterium that is the etiologic agent for localized aggressive periodontitis (LAP). LAP is a destructive and aggressive disease of the oral cavity that affects adolescents. The incidence of LAP varies among population groups, but afflicts minorities and the underprivileged at a higher frequency. Failure to treat LAP results in the loss of teeth and other health-related problems. In addition, A. actinomycetemcomitans is part of the HACEK group of bacteria that causes infective endocarditis, a disease of heart valves and tissue. A. actinomycetemcomitans secretes a protein toxin known as leukotoxin. Leukotoxin destroys leukocytes of humans, and likely plays a significant role in the pathogenesis of A. actinomycetemcomitans by helping the bacterium evade the immune response. Leukotoxin is an RTX (repeats in toxin) toxin that includes other important toxins such as E. coil alpha-hemolysin, M. haemolytica leukotoxin, B. pertussis adenylate cyclase, and V. cholerae RTX toxin. To date, little is known about how A. actinomycetemcomitans leukotoxin is produced, activated, and secreted from bacterial cells. In addition, none of the RTX toxins have been crystallized to have their three-dimensional structures solved. Proposed here are experiments that will (1) identify the genes that are required for production of active leukotoxin, (2) study the genes and proteins using genetic and biochemical approaches, and (3) grow crystals of leukotoxin and solve its three-dimensional structure at the atomic level. We expect this work to lead to a better understanding of leukotoxin production and how the toxin contributes to disease. The structural information gained through these experiments will shed more light on the mechanism of action of this important class of toxins. This new information may lead to the design of therapeutic agents that can disrupt leukotoxin activity and ultimately treat or prevent disease.
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