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Research Article

Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells

Xiao-Cui Luo, Zhen-Huang Chen, Jian-Bo Xue, Dong-Xiao Zhao, Chen Lu, Yi-Hong Li, Song-Min Li, Ya-Wen Du, Qun Liu, Ping Wang, Mingyuan Liu, and Liquan Huang
  1. aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
  2. bBiosensor National Special Lab, Key Lab for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, Zhejiang University, 310027 Hangzhou, China;
  3. cKey Lab of Zoonosis Research, Institute of Zoonosis, Jilin University, 130062 Changchun, China;
  4. dCollege of Veterinary Medicine, Jilin University, 130062 Changchun, China;
  5. eMonell Chemical Senses Center, Philadelphia, PA 19104

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PNAS March 19, 2019 116 (12) 5564-5569; first published February 28, 2019; https://doi.org/10.1073/pnas.1812901116
Xiao-Cui Luo
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Zhen-Huang Chen
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Jian-Bo Xue
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Dong-Xiao Zhao
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Chen Lu
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Yi-Hong Li
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Song-Min Li
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Ya-Wen Du
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Qun Liu
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
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Ping Wang
bBiosensor National Special Lab, Key Lab for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, Zhejiang University, 310027 Hangzhou, China;
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Mingyuan Liu
cKey Lab of Zoonosis Research, Institute of Zoonosis, Jilin University, 130062 Changchun, China;
dCollege of Veterinary Medicine, Jilin University, 130062 Changchun, China;
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Liquan Huang
aCollege of Life Sciences, Zhejiang University, 310058 Hangzhou, China;
eMonell Chemical Senses Center, Philadelphia, PA 19104
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  • For correspondence: huangliquan@zju.edu.cn
  1. Edited by Lora V. Hooper, The University of Texas Southwestern, Dallas, TX, and approved February 4, 2019 (received for review July 27, 2018)

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Significance

Intestinal tuft cells are sentinels monitoring the luminal contents and play a critical role in type 2 immunity. In this work, Trichinella spiralis excretion–secretion and extract were shown to directly induce interleukin 25 (IL-25) release from the intestinal villi, evoke calcium responses in tuft cells, and activate Tas2r bitter-taste receptors, whereas the bitter compound salicin was shown to activate and induce tuft cells to release IL-25. Gα-gustducin/Gβ1γ13 and/or Gαo/Gβ1γ13, Plcβ2, Ip3r2, and Trpm5 comprise the signal transduction pathways that tuft cells utilize to initiate type 2 immune responses. Potentiation of Trpm5 by a natural sweet compound, stevioside, can enhance the tuft cell–ILC2 circuit’s activity, indicating that modulating these signaling components can help devise new means of combating parasites.

Abstract

The parasitic helminth Trichinella 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 of T. spiralis can 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. spiralis infection 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.

  • α-gustducin
  • Gαo
  • Gβ1γ13
  • Ip3r2
  • type 2 immunity

Footnotes

  • ↵1To whom correspondence should be addressed. Email: huangliquan{at}zju.edu.cn.
  • Author contributions: X.-C.L. and L.H. designed research; X.-C.L., Z.-H.C., J.-B.X., D.-X.Z., C.L., Y.-H.L., S.-M.L., Y.-W.D., Q.L., P.W., M.L., and L.H. performed research; X.-C.L., Z.-H.C., and L.H. analyzed data; and X.-C.L., Z.-H.C., and L.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1812901116/-/DCSupplemental.

  • Copyright © 2019 the Author(s). Published by PNAS.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells
Xiao-Cui Luo, Zhen-Huang Chen, Jian-Bo Xue, Dong-Xiao Zhao, Chen Lu, Yi-Hong Li, Song-Min Li, Ya-Wen Du, Qun Liu, Ping Wang, Mingyuan Liu, Liquan Huang
Proceedings of the National Academy of Sciences Mar 2019, 116 (12) 5564-5569; DOI: 10.1073/pnas.1812901116

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Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells
Xiao-Cui Luo, Zhen-Huang Chen, Jian-Bo Xue, Dong-Xiao Zhao, Chen Lu, Yi-Hong Li, Song-Min Li, Ya-Wen Du, Qun Liu, Ping Wang, Mingyuan Liu, Liquan Huang
Proceedings of the National Academy of Sciences Mar 2019, 116 (12) 5564-5569; DOI: 10.1073/pnas.1812901116
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