This grant seeks to understand the interactions between intestinal helminth infection and type 2 immune responses that drive re-modeling of the intestinal epithelial barrier. Although type 2 immunity has been long- associated with adaptive, chronic helminth intestinal infections, host protection is largely ineffective, and worms continue to sustain egg-laying for months to years. The discovery of Group 2 innate lymphoid cells, or ILC2s, by my group and others in 2010, opened new areas of research that uncovered physiologic processes associated with type 2 immune cytokines relevant to metabolic and tissue homeostasis, suggesting the alternative narrative that evolutionarily adapted parasites co-opt integral homeostatic pathways in order to sustain chronic infection, access host nutrients, and preserve tissue integrity necessary to maintain transmission of off-spring. In prior support from this grant, we discovered that tuft cells, rare mucosal epithelial cells, are the source of IL-25, a key cytokine involved in activation of tissue ILC2s to release type 2 cytokines. After intestinal helminth infection, mice activate lamina propria ILC2s to secrete IL-13, which alters progenitor cell fate in intestinal crypts toward secretory cells, particularly tuft cells and goblet cells, thus identifying a critical tuft cell ? ILC2 circuit that integrates type 2 immunity with tissue homeostasis. In this renewal, we propose to understand this circuit in order to be able to manipulate it in directions that curtail helminth infection while preserving bowel integrity. The three Specific Aims involve defining the necessity for circuit activation to sustain chronic parasitization; outlining the mechanisms underlying the small intestinal changes in physiology that result from chronic circuit activation; and uncovering endogenous regulatory elements in the circuit that are circumvented by parasites in order to maintain chronic activation of the tuft cell ? ILC2 circuit. We believe that understanding these basic pathways has great potential not only for control of parasitic helminthes, but also to impact many diseases of intestinal dysfunction that remain of importance to humans.
Soil-transmitted helminthes constitute a substantial burden to human, animal and crop health throughout the world. The host immune response to these organisms is largely ineffective, and parasitic worms continue to lay eggs for many months and years, and eventually cause damage to tissues and health. This proposal seeks greater understanding of the mechanisms driving these tissue responses, and how to re-direct them.
| Nusse, Ysbrand M; Savage, Adam K; Marangoni, Pauline et al. (2018) Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559:109-113 |
| Ricardo-Gonzalez, Roberto R; Van Dyken, Steven J; Schneider, Christoph et al. (2018) Tissue signals imprint ILC2 identity with anticipatory function. Nat Immunol 19:1093-1099 |
| Nadjsombati, Marija S; McGinty, John W; Lyons-Cohen, Miranda R et al. (2018) Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit. Immunity 49:33-41.e7 |
| Van Dyken, Steven J; Locksley, Richard M (2018) Chitins and chitinase activity in airway diseases. J Allergy Clin Immunol 142:364-369 |
| Schneider, Christoph; O'Leary, Claire E; von Moltke, Jakob et al. (2018) A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling. Cell 174:271-284.e14 |
| Miller, Corey N; Proekt, Irina; von Moltke, Jakob et al. (2018) Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559:627-631 |
| Van Dyken, Steven J; Liang, Hong-Erh; Naikawadi, Ram P et al. (2017) Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease. Cell 169:497-509.e13 |
| Savage, Adam K; Liang, Hong-Erh; Locksley, Richard M (2017) The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine. J Immunol 199:1912-1922 |
| Singh, Priti B; Pua, Heather H; Happ, Hannah C et al. (2017) MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation. J Exp Med 214:3627-3643 |
| von Moltke, Jakob; O'Leary, Claire E; Barrett, Nora A et al. (2017) Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J Exp Med 214:27-37 |
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