Research Interests
Campylobacter jejuni is one of the most commonly reported causes of diarrhea worldwide. The ability of C. jejuni to cause disease is both complex and multi-factorial. Potential virulence determinants include toxins, adherence factors (adhesins), and entry-promoting molecules (invasins). The ability of C. jejuni to bind to cells lining the gastrointestinal tract is proposed to be essential for the development of C. jejuni-mediated enteritis. In addition, the dysentery associated with Campylobacter infection, coupled with the presence of C. jejuni in mucosal cells of infected individuals, has led investigators to hypothesize that C. jejuni enteritis is directly related to the organism’s ability to invade the cells lining the gastrointestinal tract. Entering host cells enables bacteria to evade innate host immune responses including complement activity and phagocytosis by professional phagocytes.
Research in the Konkel laboratory focuses on the characterization of C. jejuni-host cell interactions with the aim of identifying and characterizing binding and entry-promoting proteins. We have cloned and partially characterized a 37 kDa protein from C. jejuni, termed CadF, that mediates the binding of C. jejuni to fibronectin (Fn). CadF is conserved among all C. jejuni and C. coli isolates tested to date. Other work in the lab has revealed that C. jejuni synthesize and secrete proteins upon cultivation with mammalian cells. These secreted bacterial proteins are called the Campylobacter invasion antigens (Cia). A mutation in the gene encoding a 73 kDa secreted protein (CiaB) results in a non-invasive phenotype. Several different approaches (i.e., comparative and functional genomics, microarrays, and proteomics) are currently being used to identify and characterize additional C. jejuni virulence genes and their products.
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Fig. 1. Model of C. jejuni binding and entry into host cells. Intimate binding of C.
jejuni is mediated by multiple adhesins, including CadF and PEB1, and is a requirement for internalization. CadF binds Fn, which in turn binds to host cell a 5 b 1 integrin receptors. The binding of C.
jejuni to cell-associated Fn promotes and stabilizes integrin clustering, which in turn stimulates the co-clustering of focal adhesion cytoskeletal elements and cellular signaling molecules. Additional assays revealed that the binding of C.
jejuni to cell-associated Fn leads to the phosphorylation of paxillin. A subset of the newly synthesized Cia proteins are secreted and translocated into the cytoplasm of target cells upon the irreversible binding of C.
jejuni to the intestinal epithelial cells. These translocated bacterial proteins presumably stimulate host cell signaling events, promoting C.
jejuni uptake. The binding of C. jejuni to host cells is, in itself, able to induce IL-8 secretion.
Dr. Michael Konkel