* To yield new, crucial information on the pathogenesis of Vibrio cholerae infection as a necessary basis for creating effective vaccines: role and dual function of the zonula occludens toxin (ZOT) encoded by the V. cholerae filamentous phage CTX(.
* To design dynamic models for persistence of primary infection events and secondary transmission of the infection in critical geographic areas for the recurrent spreading of the disease.
* The role of ZOT toxin in modulating biochemical modifications of tight junctions up to their disassembly in intestinal epithelium will be characterized;
* ZOT diarrhoegenicity in comparison with cholera toxin will be established;
* Environmental factors and genetic components regulating expression of zot gene will be identified;
* The analysis of the microbiological and epidemiological data integrated into a geographic and demographic information system will identify determinants for maintenance of endemicity and for infection propagation. By combining these results with the pattern of genetic relatedness between the prevalent V. cholerae strains, dynamic models for persistence and transmission will be proposed as practical contributions for designing realistic cholera control strategies.
The studies of pathogeneis of V. cholerae infection will focus on: 1) identifying the mechanisms of action of ZOT by intracellular signalling and cytoskeleton rearrangement; 2) establishing the effect of ZOT on water and electrolyte transport via the paracellular pathway; 3) analysing the regulatory system and functions of the zot gene by TnPhoA fusions and site-directed mutagenesis.
The studies of cholera transmission will concern the screening of aquatic environments as possible V. cholerae reservoirs and epidemiological and microbiological investigations based on a Geographic Information System infrastructure (GIS). Collection of demographic baseline data, follow-up studies at the household level, and case-control studies of risk factors will be conducted in Harar (capital of Harari Regional State of Ethiopia) and towns and villages in the Somali Regional State of Ethiopia and in Somalia.
To assess genetic diversity and relationships in the V. cholerae population distributed in humans and in the environment, a high number of strains of V. cholerae (01 and non-01) from cases with different clinical features and from environmental sources will be analysed by a combination of genotypic methods.
Funding SchemeCSC - Cost-sharing contracts