The long-term goal of the studies proposed in this application is to elucidate how dendritic cells (DCs) interpret pathogen-inherent signals to promote Th1 or Th2 response development, with a particular emphasis on understanding how schistosomiasis leads to the development of a Th2 response. Schistosomiasis is a chronic infection caused by intravascular infection with trematode helminth parasites of the genus Schistosoma, which infect over 200 million people, causing serious disease in approximately 5% of these individuals. Studies from excellent mouse models indicate that host survival during acute infection is dependent on the development of a strong Th2 response, which despite its protective nature can nevertheless proceed to cause specific immunopathologies during the chronic stages of infection. Understanding how hosts recognize schistosomes and make the decision to mount Th2 responses is therefore of considerable importance. Dendritic cells are responsible for pathogen-recognition, processing pathogen-derived proteins for presentation to Th cells, and providing additional signals, amongst which are cytokines, that influence the development of responding Th cells into Th1 or Th2 cells. During schistosomiasis it is the egg stage of the parasite that induces the Th2 response, and it is now clear that DCs pulsed with molecules (""""""""SEA"""""""") from schistosome eggs also induce Th2 responses. This contrasts with the Th1 responses that are induced by DCs pulsed with bacteria or other pathogens that ligate Toll like receptors (TLRs) on DCs. TLR ligation leads to DC activation, whereas exposure of DCs to SEA inhibits activation. In this application a complementary set of cellular, biochemical and molecular techniques will be used to address the following specific aims:
Aim 1 - To define the pathway through which molecules from schistosome eggs inhibit TLR-initiated DC activation and condition DCs to drive Th2 responses;
Aim 2 - To identify TLR-initiated pathways in DCs that lead to suppression of Th2 cell development;
Aim 3 - To define the compartment into which schistosome egg antigens are delivered within DCs. The proposed work has distinct medical relevance, with the potential to facilitate the discovery of: 1) new schistosome-derived anti- inflammatory molecules; 2) methods to regulate Th2-mediated immunopathologies, and 3) rational prophylactic and therapeutic vaccine-relevant methods for promoting Th1 or Th2 responses. ? ? ?
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