The role of protease activated receptor 2 (PAR2) in the initiation and maintenance of type 2 immunity

Abstract

More 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.