Campylobacter jejuni is a significant gastrointestinal pathogen, causing acute illness that is characterized by diarrhea containing blood and leukocytes. C. jejuni requires a functional flagellar Type Three Secretion System (T3SS) to secrete proteins required for infection that we have termed Campylobacter invasion antigens (Cia). Acute infection requires Cia protein-mediated invasion of gastrointestinal epithelial cells by C. jejuni. While there has been a significant increase in our understanding of C. jejuni-host cell interactions, the mechanism used by the Cia proteins to alter host cell behavior remains unknown. This dissertation is composed of two studies that examine a newly identified secreted effector protein (CiaD) that is responsible for the stimulation of the secretion of the proinflammatory chemokine interleukin-8 (IL-8) from human intestinal epithelial cells and maximal C. jejuni host cell invasion.
The first study lead to the identification of a novel T3SS effector protein, which we termed CiaD, that is exported from the C. jejuni flagellum and delivered to the cytosol of host cells. We further showed that the host cell kinases p38 and Erk 1/2 are activated by CiaD, resulting in the secretion of interleukin-8 (IL-8) from host cells, and the maximal invasion of host cells by C. jejuni. Finally, we show that CiaD contributes to disease, as evidenced by infection of IL-10-/- knockout mice. The second study demonstrates that CiaD is involved in the activation of Erk 1/2 and that activated Erk 1/2 facilitates C. jejuni invasion by phosphorylation of cortactin on serine 405 and 418. This represents the first time that cortactin has been shown to be involved in C. jejuni invasion of host cells. These data also provided a mechanistic basis for the requirement of Erk 1/2 in C. jejuni-mediated cytoskeletal rearrangement.
|Advisor:||Konkel, Michael E.|
|Commitee:||Call, Doug R., Gloss, Lisa M., Kahn, Michael L., Minnich, Scott A.|
|School:||Washington State University|
|School Location:||United States -- Washington|
|Source:||DAI-B 75/05(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Microbiology|
|Keywords:||Bacterial pathogenesis, Campylobacter jejuni, Effector protein, Invasion, Type III secretion system, Virulence|
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