Bitter Taste Receptor T2R14 Modulates Gram-Positive Bacterial Internalization and Survival in Gingival Epithelial Cells (original) (raw)
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Genotype-specific regulation of oral innate immunity by T2R38 taste receptor
Molecular Immunology, 2015
The bitter taste receptor T2R38 has been shown to regulate mucosal innate immune responses in the upper airway epithelium. Furthermore, SNPs in T2R38 influence the sensitivity to 6-npropylthiouracil (PROP) and are associated with caries risk/protection. However, no study has been reported on the role of T2R38 in the innate immune responses to oral bacteria. We hypothesize that T2R38 regulates oral innate immunity and that this regulation is genotypespecific. Primary gingival epithelial cells carrying three common genotypes, PAV/PAV (PROP super-taster), AVI/PAV (intermediate) and AVI/AVI (non-taster) were stimulated with cariogenic bacteria Streptococcus mutans, periodontal pathogen Porphyromonas gingivalis or non-pathogen Fusobacterium nucleatum. QRT-PCR analyzed T2R38 mRNA, and T2R38-specific siRNA and ELISA were utilized to evaluate induction of hBD-2 (antimicrobial peptide), IL-1α and IL-8 in various donor-lines. Experiments were set up in duplicate and repeated three times. T2R38 mRNA induction in response to S. mutans was highest in PAV/PAV (4.3-fold above the unstimulated controls; p<0.05), while lowest in AVI/AVI (1.2-fold). In PAV/PAV, hBD-2 secretion in response to S. mutans was decreased by 77% when T2R38 was silenced. IL-1α secretion was higher in PAV/PAV compared to AVI/PAV or AVI/AVI with S. mutans stimulation, but it was reduced by half when T2R38 was silenced (p<0.05). In response to P. gingivalis, AVI/AVI showed 4.4-fold increase (p<0.05) in T2R38 expression, whereas the levels in PAV/PAV and AVI/PAV remained close to that of the controls. Secretion levels of IL-1α and IL-8 decreased in AVI/AVI in response to P. gingivalis when T2R38 was silenced (p<0.05), while the changes were not significant in PAV/PAV. Our data suggest that the regulation of gingival innate immunity by T2R38 is genotype-dependent and that the ability to induce a high level of hBD-2 by PAV/PAV carriers may be a reason for protection against caries in this group.
Journal of Clinical Investigation, 2022
Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into firstline defense mechanisms against bacterial infections of the lung.
mSystems, 2017
In the cariogenic Streptococcus mutans , competence development is regulated by the ComRS signaling system comprised of the ComR regulator and the ComS prepeptide to the competence signaling peptide XIP (Com X - i nducing p eptide). Aside from competence development, XIP signaling has been demonstrated to regulate cell lysis, and recently, the expression of bacteriocins, small antimicrobial peptides used by bacteria to inhibit closely related species. Our study further explores the effect of XIP signaling on the S. mutans transcriptome. RNA sequencing revealed that XIP induction resulted in a global change in gene expression that was consistent with a stress response. An increase in several membrane-bound regulators, including HdrRM and BrsRM, involved in bacteriocin production, and the VicRKX system, involved in acid tolerance and biofilm formation, was observed. Furthermore, global changes in gene expression corresponded to changes observed during the stringent response to amino a...
A possible role for taste receptor cells in surveying the oral microbiome
PLOS Biology
Taste receptor cells are sensory specialists that detect chemicals in food and drink. An exciting new report in PLOS Biology suggests that some taste cells could also be involved in immune surveillance like counterparts in the intestine. Taste receptor cells on the tongue are known for sensing chemical stimuli that allow us to enjoy or reject food. The sense of taste affects quality of life and nutrition as experienced by many afflicted by taste loss from cancer treatments or Coronavirus Disease 2019 (COVID-19) infection. Animals sample the environment to discriminate nutritive, often sweet foods from bitter toxins. Yet oral taste buds, composed of a heterogeneous population of taste cells, are also exposed to a diverse array of microbes second only to the gut microbiome. It's become clear that healthy and injured taste cells on the tongue communicate with the immune system. For example, taste buds express pathogen-detecting toll-like receptors, cytokines, and their receptors and respond to cytokines by altering sensory responses and modulating taste cell turnover [1-3]. An article by Qin and colleagues in PLOS Biology offers intriguing evidence that sweet-and umami-sensing taste cells in mice may also surveil the oral microbial environment [4]. Single-cell RNASeq analyses revealed that in fact, some taste cells share a gene expression profile similar to microfold (M) cells in the intestine. M cells sample the intestinal microbiome by transporting antigens from the lumen to underlying immune cells, triggering either mucosal immune responses or tolerance (Fig 1A and 1B). Taste receptor cells expressing Tas1r3 gene are a subset of type II cells bearing G-protein coupled receptors that recognize sweet and umami stimuli. A distinct pool of type II cells respond to bitter, while type I cells are glial-like and type III cells sense sour and salty tastants [5]. Compared to surrounding non-taste epithelium, Tas1r3+ cells express higher levels of M cell markers, including Spib, which encodes a critical transcription factor in M cell development. The team from the Sukamaran laboratory used RNAscope and immunohistochemistry to confirm the identity of 95% of Spib+ taste cells as T1r3+ type II taste cells (Fig 1B). Spib KO mice were key in exploring functional similarities between taste and M cells. RANKL, a member of the TNF ligand superfamily, induces intestinal M cell development and might act similarly on taste cells [3]. Indeed, RANKL increased the proportion of taste cells expressing M cell markers and up-regulated these genes in wild type but not Spib KO taste
Infection and Immunity, 2008
Streptococcus salivarius is an early colonizer of human oral and nasopharyngeal epithelia, and strain K12 has reported probiotic effects. An emerging paradigm indicates that commensal bacteria downregulate immune responses through the action on NF-B signaling pathways, but additional mechanisms underlying probiotic actions are not well understood. Our objective here was to identify host genes specifically targeted by K12 by comparing their responses with responses elicited by pathogens and to determine if S. salivarius modulates epithelial cell immune responses. RNA was extracted from human bronchial epithelial cells (16HBE14O-cells) cocultured with K12 or bacterial pathogens. cDNA was hybridized to a human 21K oligonucleotide-based array. Data were analyzed using ArrayPipe, InnateDB, PANTHER, and oPOSSUM. Interleukin 8 (IL-8) and growth-regulated oncogene alpha (Gro␣) secretion were determined by enzyme-linked immunosorbent assay.
Infection and Immunity, 2008
Streptococcus salivarius is an early colonizer of human oral and nasopharyngeal epithelia, and strain K12 has reported probiotic effects. An emerging paradigm indicates that commensal bacteria downregulate immune responses through the action on NF-B signaling pathways, but additional mechanisms underlying probiotic actions are not well understood. Our objective here was to identify host genes specifically targeted by K12 by comparing their responses with responses elicited by pathogens and to determine if S. salivarius modulates epithelial cell immune responses. RNA was extracted from human bronchial epithelial cells (16HBE14O-cells) cocultured with K12 or bacterial pathogens. cDNA was hybridized to a human 21K oligonucleotide-based array. Data were analyzed using ArrayPipe, InnateDB, PANTHER, and oPOSSUM. Interleukin 8 (IL-8) and growth-regulated oncogene alpha (Gro␣) secretion were determined by enzyme-linked immunosorbent assay. It was demonstrated that S. salivarius K12 specifically altered the expression of 565 host genes, particularly those involved in multiple innate defense pathways, general epithelial cell function and homeostasis, cytoskeletal remodeling, cell development and migration, and signaling pathways. It inhibited baseline IL-8 secretion and IL-8 responses to LL-37, Pseudomonas aeruginosa, and flagellin in epithelial cells and attenuated Gro␣ secretion in response to flagellin. Immunosuppression was coincident with the inhibition of activation of the NF-B pathway. Thus, the commensal and probiotic behaviors of S. salivarius K12 are proposed to be due to the organism (i) eliciting no proinflammatory response, (ii) stimulating an anti-inflammatory response, and (iii) modulating genes associated with adhesion to the epithelial layer and homeostasis. S. salivarius K12 might thereby ensure that it is tolerated by the host and maintained on the epithelial surface while actively protecting the host from inflammation and apoptosis induced by pathogens.
Inflammation induces bitter taste oversensitization via epigenetic changes inTas2rgene clusters
bioRxiv (Cold Spring Harbor Laboratory), 2023
T2R bitter receptors, encoded by Tas2r genes, are not only critical for bitter taste signal transduction but also important for defense against bacteria and parasites. However, little is known about whether and how Tas2r gene expression are regulated. Here we show that, in an inflammation model mimicking bacterial infection, the expression of many Tas2rs are significantly up-regulated and mice displayed markedly increased neural and behavioral responses to bitter compounds. Using single-cell assays for transposase-accessible chromatin with sequencing (scATAC-seq), we found that the chromatin accessibility of Tas2rs was highly cell type specific and inflammation increased the accessibility of many Tas2rs. scATAC-seq also revealed substantial chromatin remodeling in immune response genes in taste tissue stem cells, suggesting potential long-term effects. Together, our results suggest an epigenetic mechanism connecting inflammation, Tas2r gene regulation, and altered bitter taste, which may explain heightened bitter taste that can occur with infections and cancer treatments.
T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection
2012
Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection. Conflict of interest: The authors have declared that no conflict of interest exists.
Role of the Streptococcus mutans CRISPR-Cas Systems in Immunity and Cell Physiology
Journal of Bacteriology, 2014
CRISPR-Cas systems provide adaptive microbial immunity against invading viruses and plasmids. The cariogenic bacterium Streptococcus mutans UA159 has two CRISPR-Cas systems: CRISPR1 (type II-A) and CRISPR2 (type I-C) with several spacers from both CRISPR cassettes matching sequences of phage M102 or genomic sequences of other S. mutans . The deletion of the cas genes of CRISPR1 (ΔC1S), CRISPR2 (ΔC2E), or both CRISPR1+2 (ΔC1SC2E) or the removal of spacers 2 and 3 (ΔCR1SP13E) in S. mutans UA159 did not affect phage sensitivity when challenged with virulent phage M102. Using plasmid transformation experiments, we demonstrated that the CRISPR1-Cas system inhibits transformation of S. mutans by the plasmids matching the spacers 2 and 3. Functional analysis of the cas deletion mutants revealed that in addition to a role in plasmid targeting, both CRISPR systems also contribute to the regulation of bacterial physiology in S. mutans . Compared to wild-type cells, the ΔC1S strain displayed d...
PLOS ONE, 2015
The impact of commensal bacteria in eukaryotic transcriptional regulation has increasingly been demonstrated over the last decades. A multitude of studies have shown direct effects of commensal bacteria from local transcriptional activity to systemic impact. The commensal bacterium Streptococcus salivarius is one of the early bacteria colonizing the oral and gut mucosal surfaces. It has been shown to down-regulate nuclear transcription factor (NF-кB) in human intestinal cells, a central regulator of the host mucosal immune system response to the microbiota. In order to evaluate its impact on a further important transcription factor shown to link metabolism and inflammation in the intestine, namely PPARγ (peroxisome proliferator-activated receptor), we used human intestinal epithelial cell-lines engineered to monitor PPARγ transcriptional activity in response to a wide range of S. salivarius strains. We demonstrated that different strains from this bacterial group share the property to inhibit PPARγ activation independently of the ligand used. First attempts to identify the nature of the active compounds showed that it is a low-molecular-weight, DNase-, proteases-and heat-resistant metabolite secreted by S. salivarius strains. Among PPARγtargeted metabolic genes, I-FABP and Angptl4 expression levels were dramatically reduced in intestinal epithelial cells exposed to S. salivarius supernatant. Both gene products modulate lipid accumulation in cells and down-regulating their expression might consequently affect host health. Our study shows that species belonging to the salivarius group of streptococci impact both host inflammatory and metabolic regulation suggesting a possible role in the host homeostasis and health. ) and the ANR Blanc FunMetaGen. BC was a recipient of a grant from the ministère de la Recherche et de l'Education Nationale (ED425). thought to be purely digestive and protective by building a competitive barrier against pathogen colonization. Research performed over the last decades has given rise to an emergent awareness that the function of the GIT along with its microbiota also strongly influences host physiology, locally and at a systemic level contributing largely to the host health and wellbeing (for review see ). The interface between commensal bacteria and the host epithelium is crucial for the establishment of this interaction in a homeostatic and mutualistic manner. With a large genetic pool (over 150 time larger than the Human genome), the microbiota is highly adapted for intestinal fermentation of non-digestible foodstuff . On top of this important fermentative role it contributes to the development of the local and systemic immune system, to the regulation of host fat storage and even to behavior . Strong correlations between the microbiota, low-grade inflammation and host metabolism have been highlighted recently . However, the understanding of underlying mechanisms by which the gut microbiota could contribute to the host metabolic homeostasis or functions remains fragmentary.