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News
Dr.
Scott Kachlany Receives Award From NIDCR
Dr.
Scott Kachlany, of the Center for Oral Infectious Diseases, Department
of Oral Biology, is the recipient of a 5-year, $250,000 RO1 NIH/NIDCR
grant for "Leukotoxin production by A. actinomycetemcomitans".
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. coli 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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