TAS2R38 is a novel modifier gene in patients with cystic fibrosis

Castaldo, Alice; Cernera, Gustavo; Iacotucci, Paola; Cimbalo, Chiara; Gelzo, Monica; Comegna, Marika; Lullo, Antonella Miriam Di; Tosco, Antonella; Carnovale, Vincenzo; Raia, Valeria; Amato, Felice

doi:10.1038/s41598-020-62747-9

Cited by 27 publications

(21 citation statements)

References 46 publications

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“…Interestingly, a recent study has demonstrated that the frequency of the PAV allele of TAS2R38 was significantly reduced not only in the CF population with nasal polyps requiring surgery, but also in CF patients with chronic pulmonary colonisation by P. aeruginosa. These data suggest a role for TAS2R38 as a novel modifier of sinonasal disease severity and of pulmonary P. aeruginosa colonisation in people with CF [ 95 ]. Similar to that observed in the upper respiratory tract, TAS2R-dependent defence mechanisms were detected in its lower parts [ 96 , 97 ].…”

Section: Extra-oral Expression Of the Bitter Taste—role In (Patho)physiological Processesmentioning

confidence: 99%

An update on extra-oral bitter taste receptors

Tuzim

Korolczuk

2021

J Transl Med

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Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.

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Section: Extra-oral Expression Of the Bitter Taste—role In (Patho)physiological Processesmentioning

confidence: 99%

An update on extra-oral bitter taste receptors

Tuzim

Korolczuk

2021

J Transl Med

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“…Apart from these structural predispositions, infection with P. aeruginosa clearly induced comparable lipid peroxidation in both wt and CFTR-knockout mice, and this was reproduced in isolated human airway epithelial cells expressing wtCFTR or F508del-CFTR. The recently identified novel modifier gene TAS2R38 that was identified in patients with cystic fibrosis, may have a significant impact on chronic lung colonization by P. aeruginosa [30,31]. Lipid peroxidation induced ferroptotic cell death that could be antagonized by antioxidants and ferrostatin-1.…”

Section: Discussionmentioning

confidence: 99%

P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways

2021

Cell Physiol Biochem

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BACKGROUND/AIMS: Oxidative stress and infections by Pseudomonas aeruginosa (P. aeruginosa) are prominent in lungs of patients suffering from cystic fibrosis (CF). METHODS: The present study examines effects of P. aeruginosa on lipid peroxidation in human and mouse lungs, and cell death induced by P. aeruginosa in human airway epithelial cells. The role of the Ca2+ activated Cl- channel TMEM16A, the phospholipid scramblase TMEM16F, and the CFTR Cl- channel for ferroptotic cell death is examined. RESULTS: Lipid peroxidation was detected in human CF lungs, which correlated with bacterial infection. In vivo inoculation with P. aeruginosa or Staphylococcus aureus (S. aureus) induced lipid peroxidation in lungs of mice lacking expression of CFTR, and in lungs of wild type animals. Incubation of CFBE human airway epithelial cells with P. aeruginosa induced an increase in reactive oxygen species (ROS), causing lipid peroxidation and cell death independent of expression of wt-CFTR or F508del-CFTR. Knockdown of TMEM16A attenuated P. aeruginosa induced cell death. Antioxidants such as coenzyme Q10 and idebenone as well as the inhibitor of ferroptosis, ferrostatin-1, inhibited P. aeruginosa-induced cell death. CFBE cells expressing wtCFTR, but not F508del-CFTR, activated a basal Cl- conductance upon exposure to P. aeruginosa, which was caused by an increase in intracellular basal Ca2+ concentrations and activation of Ca2+-dependent adenylate cyclase. CONCLUSION: The data suggest an intrinsic pro-inflammatory phenotype in CF epithelial cells, while ferroptosis is observed in both non-CF and CF epithelial cells upon infection with P. aeruginosa. CF cells fail to activate fluid secretion in response to infection with P. aeruginosa. The use of antioxidants and inhibitors of ferroptosis is proposed as a treatment of pneumonia caused by infection with P. aeruginosa.

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“…Furthermore, another CF modifier gene, SLC6A14, affected the attachment of P. aeruginosa in both mice and humans, since it transports a bacterial attachment-promoting metabolite (l-arginine) out of the host ASL [45]. More recently, Castaldo et al related the T2R38 genotype to the severity of sinonasal disease and the occurrence of P. aeruginosa pulmonary colonisation in 210 CF patients, suggesting that T2R38, which encodes a taste receptor, is a novel modifier gene in CF [46]. These and other modifier genes contribute to the diversity of CF disease, contributing to P. aeruginosa pathogenesis and the adaptation of the bacterium to the host environment.…”

Section: Introductionmentioning

confidence: 99%

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

Sainz-Mejías

Jurado‐Martín

McClean

2020

Cells

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Pseudomonas aeruginosa is a leading cause of chronic respiratory infections in people with cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD), and acute infections in immunocompromised individuals. The adaptability of this opportunistic pathogen has hampered the development of antimicrobial therapies, and consequently, it remains a major threat to public health. Due to its antimicrobial resistance, vaccines represent an alternative strategy to tackle the pathogen, yet despite over 50 years of research on anti-Pseudomonas vaccines, no vaccine has been licensed. Nevertheless, there have been many advances in this field, including a better understanding of the host immune response and the biology of P. aeruginosa. Multiple antigens and adjuvants have been investigated with varying results. Although the most effective protective response remains to be established, it is clear that a polarised Th2 response is sub-optimal, and a mixed Th1/Th2 or Th1/Th17 response appears beneficial. This comprehensive review collates the current understanding of the complexities of P. aeruginosa-host interactions and its implication in vaccine design, with a view to understanding the current state of Pseudomonal vaccine development and the direction of future efforts. It highlights the importance of the incorporation of appropriate adjuvants to the protective antigen to yield optimal protection.

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TAS2R38 is a novel modifier gene in patients with cystic fibrosis

Cited by 27 publications

References 46 publications

An update on extra-oral bitter taste receptors

An update on extra-oral bitter taste receptors

P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

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