Human campylobacter infections have been increasingly recognized ass major causes of human illness. Campylobacter jejuni is now recognized as the most common bacterial cause of invasive diarrhea in the United States. Campylobacter fetus has been identified as a cause of bacteremia and disseminated infection particularly in immunocompromised hosts, such as patients with AIDS, neonates, and patients with alcoholic liver disease. Although Campylobacter jejuni is infrequently isolated from the blood, C. fetus is primarily a bloodstream isolate. The difference in invasive potential of these two Campylobacter species may relate to the finding that C. fetus is generally resistant to the bactericidal effect of human serum while C. jejuni is serum-sensitive. C. fetus generally have a smooth or complete lipopolysaccharide (LPS) layer in their outer membranes. A smooth LPS is known to confer serum-resistance to other enteric bacterial organisms; however, serum-sensitive strains of C. fetus also express a complete LPS implying that other factors contribute to serum-resistance. This proposal explores the mechanisms of serum-resistance of C. fetus, and the relationship with high molecular weight surface-array proteins that migrate at 100k, 125k, or 138k. Preliminary data indicate that the presence of these surface-array proteins is responsible for the serum-and phagocytosis-resistance observed because of failure of C3b to bind to the encapsulated C. fetus strains. We plan to characterize the biological properties of C. fetus strains with or without these surface proteins in relation to growth conditions, complement and phagocytosis-resistance, and immunological relationships. Subsequently we plan to continue our chemical and immunological characterization of the proteins themselves. An important question to be answered is the mechanism by which these proteins activate C3 but prohibit C3b from binding to the bacterial cell surface. Using a previously developed mouse model we will assay the virulence of naturally and experimentally encapsulated and unencapsulated C. fetus strains. Using the purified proteins, and monospecific rabbit antisera and mouse-derived monoclonal antibodies, we will establish their role in virulence in the mouse model. Then we will attempt to understand the genetics of production of these proteins. First we will explore the relationship with plasmids and then using on of several methods we will clone the genes responsible for production and expression of these proteins.
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