IL4R and Immunity to GI Nematode Parasites

GI nematode parasites infect approximately 1 billion people worldwide and cause considerable morbidity and mortality. Studies in mice have demonstrated that mast cells participate in host defense against some GI nematode parasites, such as Trichinella spiralis, but are not involved in host defense against other GI nematode parasites, such as Nippostrongylus brasiliensis. More recent studies demonstrate that host protection against both of these parasites depends on IL-4 and IL-13 ligation of receptors (R) that contain the IL-4Ra polypeptide and activate the signaling molecule, Stat6. IL-13 is more important than IL-4 for protection against N. brasiliensis, even though IL-4, but not IL- 13, stimulates mouse B and T cells and IL-4 binds to both the IL-4R and the IL-13R, while IL-13 only binds to the IL-13R.
<P>Experiments with mice will now test the hypotheses that:

<OL><LI>IL-13 is more important than IL-4 for protective immunity against N.brasiliensis because the cells most directly responsible for expelling this parasite express considerable IL-13R but little IL-4R, and IL-13 is a more potent ligand than IL-4 for the IL-13R;
<LI> IL-13 is a general requirement for host protection against GI nematode parasites; and
<li>Mast cells and Stat6 signaling are independent requirements for host protection against T. spiralis that are both necessary to induce changes in host GI physiology that may lead to worm expulsion.
</ol>Experiments will follow the course of infection and the immune responses to infection in wild-type, IL-4- deficient, Stat6-deficient, and IL-4Ra-deficient mice and determine the effects of IL-3, IL-4, and IL-13, as well as antibodies to IL-4Ra, common g chain, IL-13Ra1, and c-kit, on the course of parasite infection. The use of two different parasites will allow questions to be asked about the importance of IL-13 in worm expulsion and about interactions between mast cells and Stat6 signaling in the experimental systems that are most likely to provide clear answers. In vivo cytokine production will be determined by a novel cytokine capture assay, mast cell activation will be determined by measurement of serum levels of intestinal mast cell protease, and contributions made by different cell types to protective immunity will be determined by irradiation/ reconstitution experiments.
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We expect that our results will demonstrate a common proximal pathway of host defense against GI nematode parasites that activates more than one defense mechanism, and that different Stat6-dependent distal defense mechanisms are important for host protection against different GI nematode parasites.