Campylobacter jejuni & Inflammation

Summary

Campylobacter jejuni is the most common cause of bacterial foodborne disease. Yet, little is known about how this pathogen causes intestinal inflammation. The clinical pathology during human infection points to invasive bacterial behavior accompanied by the induction of potent pro-inflammatory responses. However, research on the pathogenesis of C. jejuni has been hampered by its highly variable behavior in vitro and the lack of a suitable animal model of infection. The aim of the study described in this thesis was to better understand Campylobacter pathogenesis by focusing on the molecular events that drive the direct interaction of the pathogen with epithelial cells and macrophages, and its interaction with the innate immune system. These topics were selected as our lab recently discovered that C. jejuni displays highly invasive behavior under conditions of specific nutrient limitation and that C. jejuni is able to elicit a powerful innate immune response in in vitro cell systems. In our study, we discovered that C. jejuni invades epithelial cells via a novel mechanism independent of the very common actin filament or microtubules-mediated cellular uptake processes. After this highly efficient invasion process, C. jejuni enters the endolysosomal pathway. In addition, we discovered a novel Campylobacter-specific pathogen-associated molecular patterns secreted by C. jejuni that induces a potent inflammatory immune response in epithelial cells. This response was independent of Toll-like receptors and Nod-like receptors. The discovery of a C. jejuni-specific innate immune agonist fits with the emerging concept of the existence of bacterial species-specific immune stimuli that contribute to the innate immune response and could be of great importance in C. jejuni pathogenesis. Finally, we demonstrated for the first time that C. jejuni activates the NLRP3 inflammasome in macrophages. Inflammasome activation resulted in the secretion of the potent inflammatory cytokine IL-1β and thus may provide a molecular basis for the presence of high levels of this cytokine in patients during C. jejuni infection. Overall, our results support the scenario that C. jejuni is capable of invading epithelial cells while the host senses the pathogen through different innate immune pathways, generating the potent pro-inflammatory environment typically present during natural symptomatic infection. The interaction with the innate immune system may play a major role in C. jejuni pathogenesis and could contribute to the observed pathology. Together our findings increase the understanding of the mechanisms through which C. jejuni causes disease and will advance the development of novel therapeutic intervention strategies.

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