scholarly journals Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Katie A. Hildersley ◽  
Tom N. McNeilly ◽  
Victoria Gillan ◽  
Thomas D. Otto ◽  
Stephan Löser ◽  
...  
Keyword(s):  
Mouse Models ◽  
Taste Receptor ◽  
Economic Problem ◽  
Effective Vaccine ◽  
Parasitic Nematodes ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Parasite Infections ◽  
Host Parasite

Helminth parasite infections of humans and livestock are a global health and economic problem. Resistance of helminths to current drug treatment is an increasing problem and alternative control approaches, including vaccines, are needed. Effective vaccine design requires knowledge of host immune mechanisms and how these are stimulated. Mouse models of helminth infection indicate that tuft cells, an unusual type of epithelial cell, may ‘sense’ infection in the small intestine and trigger a type 2 immune response. Currently nothing is known of tuft cells in immunity in other host species and in other compartments of the gastrointestinal (GI) tract. Here we address this gap and use immunohistochemistry and single cell RNA-sequencing to detail the presence and gene expression profile of tuft cells in sheep following nematode infections. We identify and characterize tuft cells in the ovine abomasum (true stomach of ruminants) and show that they increase significantly in number following infection with the globally important nematodes Teladorsagia circumcincta and Haemonchus contortus. Ovine abomasal tuft cells show enriched expression of tuft cell markers POU2F3, GFI1B, TRPM5 and genes involved in signaling and inflammatory pathways. However succinate receptor SUCNR1 and free fatty acid receptor FFAR3, proposed as ‘sensing’ receptors in murine tuft cells, are not expressed, and instead ovine tuft cells are enriched for taste receptor TAS2R16 and mechanosensory receptor ADGRG6. We also identify tuft cell sub-clusters at potentially different stages of maturation, suggesting a dynamic process not apparent from mouse models of infection. Our findings reveal a tuft cell response to economically important parasite infections and show that while tuft cell effector functions have been retained during mammalian evolution, receptor specificity has diverged. Our data advance knowledge of host-parasite interactions in the GI mucosa and identify receptors that may potentiate type 2 immunity for optimized control of parasitic nematodes.

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

2019 ◽  
Vol 116 (12) ◽  
pp. 5564-5569 ◽  
Author(s):  
Xiao-Cui Luo ◽  
Zhen-Huang Chen ◽  
Jian-Bo Xue ◽  
Dong-Xiao Zhao ◽  
Chen Lu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Bitter Taste ◽  
Trichinella Spiralis ◽  
Taste Receptor ◽  
Taste Bud ◽  
Tuft Cell ◽  
Tuft Cells

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.

scholarly journals Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

2018 ◽  
Vol 115 (21) ◽  
pp. 5552-5557 ◽  
Author(s):  
Weiwei Lei ◽  
Wenwen Ren ◽  
Makoto Ohmoto ◽  
Joseph F. Urban ◽  
Ichiro Matsumoto ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Mucosal Immunity ◽  
Cell Activation ◽  
Nippostrongylus Brasiliensis ◽  
Infectious Agents ◽  
Cell Hyperplasia ◽  
Type 2 Immunity ◽  
Tuft Cell ◽  
Tuft Cells

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

scholarly journals Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

2018 ◽  
Author(s):  
Marija S. Nadjsombati ◽  
John W. McGinty ◽  
Miranda R. Lyons-Cohen ◽  
Joshua L. Pollack ◽  
G.A. Nagana Gowda ◽  
...  
Keyword(s):  
Small Intestine ◽  
Immune Responses ◽  
Innate Immune ◽  
Nippostrongylus Brasiliensis ◽  
Transduction Pathway ◽  
Type 2 Immunity ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Taste Transduction

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

scholarly journals Small Intestinal Tuft Cell Activity Associates With Energy Metabolism in Diet-Induced Obesity

2021 ◽  
Vol 12 ◽  
Author(s):  
Pankaj Arora ◽  
Daniel Andersen ◽  
Janne Marie Moll ◽  
Niels Banhos Danneskiold-Samsøe ◽  
Liqin Xu ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Body Mass ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Small Intestinal

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.

scholarly journals Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically drive lung type 2 inflammation

2021 ◽  
Author(s):  
Saltanat Ualiyeva ◽  
Evan R Lemire ◽  
Amelia Boyd ◽  
Caitlin Wong ◽  
Juying Lai ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Innate Immune ◽  
Cysteinyl Leukotrienes ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Lung Eosinophilia ◽  
Type 2 Inflammation

Aeroallergen sensing by airway epithelial cells can trigger pathogenic immune responses leading to chronic type 2 inflammation, the hallmark of airway diseases such as asthma. Airway tuft cells are specialized chemosensory epithelial cells and the dominant source of the epithelial cytokine IL-25 in the trachea and of cysteinyl leukotrienes (CysLTs) in the naive murine nasal mucosa. The interaction of IL-25 and CysLTs and the contribution of tuft cell-derived CysLTs to the development of allergen-triggered inflammation in the airways has not been clarified. Here we show that inhalation of LTC4 in combination with a subthreshold dose of IL25 leads to dramatic synergistic induction of type 2 inflammation throughout the lungs, causing rapid eosinophilia, dendritic cell (DC) and inflammatory type 2 innate lymphoid cell (ILC2) expansion, and goblet cell metaplasia. While lung eosinophilia is dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells require signaling through both CysLT1R and CysLT2R. Tuft cell-specific deletion of the terminal enzyme requisite for CysLT production, Ltc4s, was sufficient to reduce both the innate immune response in the lung: eosinophilia, ILC2 activation and DC recruitment, and the systemic immune response in the draining lymph nodes after inhalation of the mold aeroallergen Alternaria. Our findings identify surprisingly potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.

scholarly journals Enteric Tuft Cells in Host-Parasite Interactions

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1163
Author(s):  
Sruthi Rajeev ◽  
Olivia Sosnowski ◽  
Shuhua Li ◽  
Thibault Allain ◽  
André G. Buret ◽  
...  
Keyword(s):  
Parasitic Infection ◽  
Neuronal Cell ◽  
Parasitic Infections ◽  
Current State ◽  
Host Parasite Interactions ◽  
Tuft Cell ◽  
Tuft Cells ◽  
Inflammatory Bowel ◽  
Irritable Bowel ◽  
Host Parasite

Enteric tuft cells are chemosensory epithelial cells gaining attention in the field of host-parasite interactions. Expressing a repertoire of chemosensing receptors and mediators, these cells have the potential to detect lumen-dwelling helminth and protozoan parasites and coordinate epithelial, immune, and neuronal cell defenses against them. This review highlights the versatility of enteric tuft cells and sub-types thereof, showcasing nuances of tuft cell responses to different parasites, with a focus on helminths reflecting the current state of the field. The role of enteric tuft cells in irritable bowel syndrome, inflammatory bowel disease and intestinal viral infection is assessed in the context of concomitant infection with parasites. Finally, the review presents pertinent questions germane to understanding the enteric tuft cell and its role in enteric parasitic infections. There is much to be done to fully elucidate the response of this intriguing cell type to parasitic-infection and there is negligible data on the biology of the human enteric tuft cell—a glaring gap in knowledge that must be filled.

scholarly journals Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zheng Fu ◽  
Joseph W. Dean ◽  
Lifeng Xiong ◽  
Michael W. Dougherty ◽  
Kristen N. Oliff ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Th17 Cells ◽  
Tissue Remodeling ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Tuft Cell ◽  
Mitochondrial Transcription Factor A

AbstractRORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

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