The Role of Type-2 IL-4 Receptor and its Downstream Genes in Nematode Infection

Abstract

Over 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.