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Abstracts
Workgroup: Frontiers in Disease Research
Intracellular Survival of Perkinsus marinus: the Oxidative Stress Pathway as a Target for Therapy.
Principal Investigator(s):
Gerardo R. Vasta, Center of Marine Biotechnology, Baltimore, MD, vasta@umbi.umd.edu
Co-Investigator(s):
E. J. Schott
Funding Period: 2001-03
We are characterizing potential targets for anti-parasite therapies in the antioxidant pathway of P. marinus. These are:
- Ascorbate peroxidase, an activity that appears to be unique to the parasite.
- Two distinct iron superoxide dismutases, PmSOD1and PmSOD2, that have unique cellular localizations. PmSOD1 in the mitochondrion, and PmSOD2 in an unknown compartment located below the plasma membrane.
- Structural information, obtained by X-ray crystallographic analysis of both PmSOD1 and PmSOD2, will be used to explore the design of structure-based chemotherapeutic agents.
- We are also actively characterizing the antioxidant repertoire of the oyster host, to evaluate how to specifically inhibit the anti-oxidant pathway of the parasite.
We have found that the parasite is highly sensitive to hypochlorite, but not to superoxide or hydrogen peroxide. Hypochlorite is the product of host MPO activity.
IMPACTS and/or BENEFITS:
These results advance the search for effective anti-P. marinus chemotherapies.
- Many successful anti-parasitic chemotherapies consist of oxidative-stress inducing compounds that are more toxic to parasite than host. Chemotherapies can be improved by a thorough understanding of oxidative stress mechanisms in both host and parasite.
- The verification that the mitochondrion is the location of a putative P. marinus virulence factor (FeSOD), synergizes with the fact that in related human parasites, therapies that inhibit mitochondrial function are highly effective.
- We have advanced in our goal to inhibit the ROS removal pathway of P. marinus, by direct enzymatic inhibitors, and disrupt the function, maturation, or subcellular localization of these enzymes. Our collaborations with experts in molecular modeling will facilitate discovery of these compounds.
- In closed systems, application of chemotherapies would be an excellent choice for production of clean seed.
- Knowledge that hypochlorite kills P. marinus suggests that a search for oysters with robust MPO activity may uncover a source of resistance to infection.
PROJECT PUBLICATIONS:
Schott, E.J., Robledo, Pecher. W.M., Okafor, F. and Vasta, G.R. Resistance of the protistan parasite Perkinsus marinus to reactive oxygen intermediates. In preparation for Journal of Experimental Parasitology
Robledo, J.A.F., Vasta, G.R. Gene characterization of Slc11a transporter in the protistan parasite Perkinsus marinus. In preparation for Molecular and Biochemical Parasitology.
Coss, C. A. 2000. Investigation of Perkinsus species from clams sympatric to oysters, with emphasis on infections in baltic clams Macoma balthica of Chesapeake Bay. Ph. D. Dissertation, The George Washington University, Washington, D.C.
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