CHOLERA: PATHOGENESIS AND IMMUNOLOGY

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The goals of this research are to contribute to the complete understanding of the pathogenesis and immunology of cholera at both the organismal and the molecular levels with the expectation that this will lead to the development of rational and effective means of immunoprophylaxis. As cholera is the prototype of an expanding number of enterotoxic enteropathies, the observations are pertinent to the larger global problem of secretory diarrheal disease. It is clear that the disease, cholera, is an effective immunizing process which presents to the human host a consortium of products elaborated by the cholera vibrios growing in vivo. These include: colonization factors (as yet undefined); surface components such as the lipopolysaccharide and outer membrane proteins; the HA/protease; other enzymes; the mannose-sensitive (El Tor biotype) and other hemagglutinins; the flagellum; and the enterotoxin. This proposal specifically addresses: the identification and characterization of factor(s) participating in adherence of Vibrio cholerae to intestinal epithelium; outer membrane antigens (particularly novel iron-regulated proteins expressed in vivo); and the definition of antigens and antibodies which may be protective [including functional domains and epitopes on the immunodominant, binding, choleragenoid (B-subunit pentamer) portion of the cholera enterotoxin]. Technology includes: bacterial binding studies; protein separation and analysis with SDS-PAGE and immunoblotting; micro-antibacterial assays involving protein components of mothers' milk, polyclonal and monoclonal antibacterial antibodies; and antitoxic monoclonal antibodies and synthetic peptides of the cholera enterotoxin with the objective of developing a synthetic vaccine.