Browsing School, Graduate by Subject "Gastrointestinal Tract"
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The role of protease activated receptor 2 (PAR2) in the initiation and maintenance of type 2 immunityMore than one third of the world's population is infected with helminths with the highest prevalence in under developed countries. It is well established that helminth infection induces a highly polarized type 2 immune response in the host that is critical for helminth expulsion; however, the mechanisms by which host immunity is initiated are poorly understood. Helminth infection up-regulation of type 2 cytokines, IL–4 and IL–13 and induces alterations in gut function including an increase in intestinal permeability and a hyper-responsiveness of smooth muscle. Helminths secrete a number of proteases that may be used as molecular mimics to interact with the host. We identified a 26 kDa “trypsin-like protease” generated by helminths that interacts with host protease activated receptor 2 (PAR2). PAR2 is expressed on structural and immune cells throughout the gut and is activated by proteolytic cleavage. Proteolytic pathways are important to immune responses, but the contribution of PAR2 to the Th2 immune response against helminth infection is poorly understood. The central hypothesis of this project is that helminth generated serine proteases activate PAR2 on host cells and play a pivotal role in the induction of host type 2 immunity. To investigate this hypothesis, we propose the following aims; (1) to determine if helminths use molecular mimicry to interact with host proteolytic pathways and (2) to elucidate the role of PAR2 in the development of the type 2-mediated protective immune response in vivo. Our results indicate that nematodes secrete a trypsin–like serine protease that activates PAR2. Sequence and sequence comparisons results demonstrate that this protease is similar to other common human trypsin–like proteases. Finally, we identified a role for PAR2 in the both early and late stages of enteric nematode infection. At early time points, PAR2 plays a role in the increased in intestinal epithelial permeability that acts to facilitate the passage of worm products across the mucosal barrier and contributes to the initial up–regulation of type 2 cytokines. At later time points, PAR2 mediates the smooth muscle response to neural stimulation that is part of the immune–mediated alterations in gut function that promote worm expulsion.
The Role of Type-2 IL-4 Receptor and its Downstream Genes in Nematode InfectionOver one third of the world's population is infected with nematodes with the highest prevalence in third world countries. It is well established that nematode infection induces a highly polarized Th2 immune response in the host that contributes to nematode expulsion. IL-13, one of the major cytokines for Th2 response, shares a common receptor with IL-4 and has overlapping physiological effects. Studies with various knockouts showed important roles of IL-4 and IL-13 in both lung and gut pathologies, but has been insufficient to distinguish the effects of these two cytokines. The central hypothesis of this project is that IL-13 acting through the type 2 IL-4R leads to activation of STAT6-dependent transcription of genes that participate in the epithelial host defense against enteric pathogens. To investigate this hypothesis, we will infect mice deficient in IL-13R?1 to examine the development and maintenance of Th2 immunity. Neutrophils have been shown to play an indirect role in modulating Th2 responses in nematode infection by eliminating bacteria associated with the invading nematodes to prevent a localized Th1 up-regulation. Neutrophil elastase, one of the IL-13/STAT6 dependent genes, is a critical component in the anti-microbial activity of neutrophils and the major protease contained in neutrophil-secreted granules and neutrophil extracellular traps (NETs). The second aim of the project will examine the role of neutrophils elastase in models of enteric nematode infection and its contribution to host immunity.