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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE016133-04S1
Application #
7434168
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2004-07-01
Project End
2009-03-31
Budget Start
2007-06-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$12,539
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Dentistry
Type
Schools of Dentistry
DUNS #
781265475
City
Newark
State
NJ
Country
United States
Zip Code
07101
Hioe, Catarina E; Tuen, Michael; Vasiliver-Shamis, Gaia et al. (2011) HIV envelope gp120 activates LFA-1 on CD4 T-lymphocytes and increases cell susceptibility to LFA-1-targeting leukotoxin (LtxA). PLoS One 6:e23202
Kachlany, Scott C; Schwartz, Amy B; Balashova, Nataliya V et al. (2010) Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells. Leuk Res 34:777-85
Forman, Michael S; Nishikubo, Jason B; Han, Rebecca K et al. (2010) Gangliosides block Aggregatibacter Actinomycetemcomitans leukotoxin (LtxA)-mediated hemolysis. Toxins (Basel) 2:2824-36
Balashova, Nataliya V; Shah, Chintan; Patel, Jigna K et al. (2009) Aggregatibacter actinomycetemcomitans LtxC is required for leukotoxin activity and initial interaction between toxin and host cells. Gene 443:42-7
Venketaraman, Vishwanath; Lin, Albert K; Le, Amy et al. (2008) Both leukotoxin and poly-N-acetylglucosamine surface polysaccharide protect Aggregatibacter actinomycetemcomitans cells from macrophage killing. Microb Pathog 45:173-80
Isaza, Maria P; Duncan, Matthew S; Kaplan, Jeffrey B et al. (2008) Screen for leukotoxin mutants in Aggregatibacter actinomycetemcomitans: genes of the phosphotransferase system are required for leukotoxin biosynthesis. Infect Immun 76:3561-8
Isaza, Maria P; Chau, Jennie T; Le, Amy et al. (2008) A bioluminescent HL-60 cell line to assay anti-leukaemia therapeutics under physiological conditions. Luminescence 23:17-21
Dileepan, T; Kachlany, S C; Balashova, N V et al. (2007) Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin. Infect Immun 75:4851-6
Balashova, Nataliya V; Park, Diane H; Patel, Jigna K et al. (2007) Interaction between leukotoxin and Cu,Zn superoxide dismutase in Aggregatibacter actinomycetemcomitans. Infect Immun 75:4490-7
Crosby, Juan A; Kachlany, Scott C (2007) TdeA, a TolC-like protein required for toxin and drug export in Aggregatibacter (Actinobacillus) actinomycetemcomitans. Gene 388:83-92

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