PATHOGENIC VIBRIO--INTESTINAL MUCOSAL INTERACTIONS

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Diarrheal diseases remain a significant worldwide cause of human morbidity and mortality, and in many developing countries may be the most common cause of death. The series of events leading to pathogenesis in infectious bacterial diarrheas are more complex than previously appreciated and involve interactions of various microbial attributes, or virulence properties, for circumventing host defenses. Particularly, the host-pathogen interactions on mucosal surfaces that lead to successful establishment of enteric and other mucosal pathogens remain largely unresolved. The proposed study will increase our knowledge of pathogen-host mucosal interactions with emphasis on the largely unexplored roles of gastrointestinal mucin secretions. Pathogenic vibrios will be used because of the wealth of knowledge that has accumulated on the toxin and several virulence determinants of V. cholerae and the growing awareness, but lack of understanding, of other pathogenic Vibrio species (non O-1 V. cholerae, V. parahemolyticus, V. fluvialis) that can produce diarrheal disease. Scanning electron microscopy will be used to determine the separate contributions of association with the epithelium or mucin to the in vivo interactions of the pathogenic vibrios with the intestinal mucosa during infection. The data will be used to help assess the validity of some often used in vitro "adherence assays". The possible role of mucin utilization during colonization will be assessed by determination of the basis for the reduced virulence of strains of a mucin non-utilizing phenotype of V. cholerae isolated by our laboratory, the enzymatic activities responsible for utilization of mucin by the wild-type strains, and the ability of purified mucin from different sources to serve as a growth substrate for V. cholerae and the other pathogenic vibrios. Changes in the rheological properties of mucin as a consequence of interactions with pathogenic vibrios also will be assessed. The role of motility (or chemotaxis) as a possible virulence factor, as suggested for V. cholerae, will be determined for the other pathogenic vibrios. If motility is a virulence determinant for the other vibrios, flagellar vaccines will be produced to determine if they, like V. cholerae flagellar vaccines, are protective immunogens.