Campylobacter jejuni is a significant human enteric pathogen that is a leading cause of bacterial gastroenteritis in both the United States and worldwide. In addition to the immediate consequences of a primary infection, a major sequelae of some C. jejuni infections is the development of Guillian-Barre Syndrome, an autoimmune neuropathy. Acute infection with C. jejuni results in a disease that can range from a self-limited watery diarrhea to a bloody dysentery-type picture. This severe presentation indicates that C. jejuni is capable of invading gut epithelial tissue; furthermore, subsequent studies with cultured gut epithelium and examination of clinical isolates from infected patients demonstrate this ability. Therefore, we hypothesize that invasion into epithelial cells is an important aspect of the pathogehesis of C. jejuni. Our preliminary studies using a genetic screen to find mutants that are incapable of invasion have identified several genes that may play a role in the invasion process. During our preliminary characterization of these mutants, two classes of invasion mutants have emerged. Class I invasion mutants are non-motile, while Class II invasion mutants are fully motile. The focus of this proposal is to elucidate the mechanisms involved in C. jejuni invasion through the characterization of the functions of several of these genes. The specific ims of this proposal are (1) characterize Class I mutants with regard to the role that motility plays in invasion, (2) investigate the role that a conserved peptidase domain found in a Class II mutant plays in invasion and (3) determine the role that a TolB homolog plays in the invasion process. Greater understanding of the invasion pathway through these studies will help identify potential targets for therapeutic intervention. A comprehensive program for career development is outlined, a scientific advisory committee for mentoring has been assembled and a plan for further study in microbial pathogenesis is presented.
