Infection by the parasitic helminthTrichinella spiralisactivates a Tas2r-mediated signaling pathway in intestinal tuft cells

Abstract

The parasitic helminthTrichinella spiralis, which poses a serious health risk to animals and humans, can be found worldwide. Recent findings indicate that a rare type of gut epithelial cell, tuft cells, can detect the helminth, triggering type 2 immune responses. However, the underlying molecular mechanisms remain to be fully understood. Here we show that both excretory–secretory products (E–S) and extract ofT. spiraliscan stimulate the release of the cytokine interleukin 25 (IL-25) from the mouse small intestinal villi and evoke calcium responses from tuft cells in the intestinal organoids, which can be blocked by a bitter-taste receptor inhibitor, allyl isothiocyanate. Heterologously expressed mouse Tas2r bitter-taste receptors, the expression of which is augmented during tuft-cell hyperplasia, can respond to the E–S and extract as well as to the bitter compound salicin whereas salicin in turn can induce IL-25 release from tuft cells. Furthermore, abolishment of the G-protein γ13 subunit, application of the inhibitors for G-protein αo/i, Gβγ subunits, and phospholipase Cβ2 dramatically reduces the IL-25 release. Finally, tuft cells are found to utilize the inositol triphosphate receptor type 2 (Ip3r2) to regulate cytosolic calcium and thus Trpm5 activity, while potentiation of Trpm5 by a sweet-tasting compound, stevioside, enhances tuft cell IL-25 release and hyperplasia in vivo. Taken together,T. spiralisinfection activates a signaling pathway in intestinal tuft cells similar to that of taste-bud cells, but with some key differences, to initiate type 2 immunity.

Existing bitter medicines for fighting 2019‐nCoV‐associated infectious diseases

“…TAS2R38 was stimulated by acyl‐homoserine lactones and gram‐negative quorum‐sensing molecules to subsequently activate nitric oxide‐dependent innate immune responses 17 . Tuft cells, a type of gut epithelial cell, can detect helminth, stimulating TAS2R to trigger type 2 immune responses 18 . Moreover, some required genes for bitter‐sensing, such as α‐gustducin and Trpm5, are also critical to initiate a type 2 immune response 30,31 .…”

“…This suggests that TAS2Rs might have functions other than bitter taste perception. Indeed, they were suggested to be involved in appetite regulation, the treatment of asthma, the regulation of gastrointestinal motility, and the control of innate immunity 14,16‐18 . TAS2Rs can be classified into broadly, narrowly, and intermediately tuned receptors according to the agonist spectra 19 .…”

Organoids – New Models for Host–Helminth Interactions

“…Specifically, mouse small intestinal organoids have served as an experimental system to demonstrate the expansion of tuft cells as a consequence of ex vivo stimulation with interleukin (IL) 13. IL-13 is secreted by innate lymphoid cells in response to stimulation with IL-25, a cytokine produced by tuft cells during the early response to in vivo infection with the intestinal dwelling nematodes Nippostrongylus brasiliensis, Heligmosomoides polygyrus, and Trichinella spiralis [36][37][38][39]. These findings Glossary Excretory/secretory (ES) products: soluble mediators released by helminths, either actively exported through secretory pathways or diffused or leaked from the parasite soma as a consequence of physiological process such as digestion.…”

“…Organoids have also been utilized in experiments that aim to characterize the interactions and intestinal epithelial responses to ES products of various nematodes. In particular, stimulation of murine small intestine organoids with ES products and extracts of T. spiralis showed that sensing of parasitic products by tuft cell receptors results in Ca 2+ responses [39]. Moreover, imaging experiments of murine small intestine and colon organoids, microinjected with exosome-like extracellular vesicles (EVs) present in the ES of N. brasiliensis and Trichuris muris, respectively, showed their internalization by host epithelial cells [42,43].…”

“…Cell lines and primary small intestine and colonic epithelial cells have also been used to study the responses of epithelial cells to H. polygyrus [49], T. muris [50,51], T. spiralis [39], and Ascaris ES products and EVs [52]. While the use of cellular preparations ex vivo allows experiments to be performed with the different cell populations present in the tissue, the isolation procedures disrupt the architecture and polarization of the cells in the tissue, making it difficult to interpret the results.…”