Description succincte
(Anglais)
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Neospora caninum and Toxoplasma gondii are obligate intracellular protozoan parasites which infect a wide range of vertebrate hosts. They are classified in the phylum Apicomplexa. In humans T. gondii causes an opportunistic disease with immune dysfunction and congenital dysfunction in infants, respectively. Re-emergence of toxoplasmosis as a life threatening disease in AIDS patients has boosted its molecular and immunological characterization. N. caninum, in contrast, represents the most important abortion-causing pathogen in cattle and causes neuromuscular disease in dogs, and is therefore of high veterinary medical and economical importance. Two strategies are currently anticipated to combat toxoplasmosis and neosporosis: vaccination and chemotherapy.
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Partenaires et organisations internationales
(Anglais)
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AT, CH, CZ, DE, DK, ES, FR, GR, IT, NL, NO, PT, SE, UK
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Résumé des résultats (Abstract)
(Anglais)
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NOVEL TOOLS FOR THE PREVENTION OR TREATMENT OF INFECTION BY THE TWO IMPORTANT APICOMPLEXAN PARASITES TOXOPLASMA GONDII AND NEOSPORA CANINUM ARE URGENTLY NEEDED. MULTIDRUG RESISTANCE PROTEIN 1 (MDR1, ABCB1, P-GLYCOPROTEIN) IS ONE OF THE MOST INTENSIVELY STUDIED MEMBRANE TRANSPORTERS. MDR1 OVEREXPRESSION, FOLLOWING DRUG TREATMENT, IS RESPONSIBLE FOR MULTIDRUG RESISTANCE IN TUMOR CELLS AND IN PATHOGENIC YEASTS, FUNGI, BACTERIA AND PARASITIC PROTOZOA, INCLUDING PLASMODIUM, LEISHMANIA, TRYPANOSOMA. IN ADDITION TO MEDIATE DRUG RESISTANCE, MDR1 ALSO PLAYS SEVERAL BUT NOT COMPLETELY ELUCIDATED ROLES IN PHYSIOLOGICAL PROCESSES IN ABSENCE OF DRUG PRESSURE. OUR RESEARCH ON TOXOPLASMA GONDII HAS FOCUSSED ON THE MDR1 ROLE DURING HOST-PATHOGEN INTERACTION. IN THIS RESPECT, THE TWO MAJOR GOALS OF OUR PROJECT ARE TO I) ELUCIDATE THE FUNCTION OF HOST MDR1 DURING PARASITE INFECTION AND TO II) CHARACTERIZE THE MDR1 HOMOLOGUE PRESENT IN T. GONDII. IN ADDITION, WE HAVE CHARACTERIZED TWO NOVEL CHEMICAL COMPOUND CLASSES (THIAZOLIDES, PENTAMIDINE-DERIVATIVES) WITH RESPECT TO THEIR EFFICACY AGAINST N. CANINUM, T. GONDII, (AND ALSO OTHER PROTOZOANS SUCH AS GIARDIA), AND WE HAVE IDENTIFIED N. CANINUM PROTEIN DISULFIDE ISOMERASE AS A NOVEL POTENTIAL DRUG TARGET FOR THE THIAZOLIDES IN THESE PARASITES. IN ADDITION, WE HAVE FOUND EVIDENCE THAT THE HOST CELLS ACTIVELY PARTICIPATE IN THE ANTIPARASITIC EFFECTS OF PENTAMIDINE DERIVATIVES, BUT HAVE NOT YET IDENTIFIED THE MOLECULAR FACTORS RESPONSIBLE FOR THESE EFFECTS. FURTHER STUDIES WERE CARRIED OUT WITH REGARD TO NOVEL VACCINE CANDIDATES IN N. CANINUM, OF WHICH ONE RHOPTRY ANTIGEN, NCROP2, SHOWED PROMISING RESULTS IN STUDIES EMPLOYING THE MOUSE MODEL.
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