Nithin D. Adappa

T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

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.

Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.

Bitter and sweet taste receptors regulate human upper respiratory innate immunity

Bitter taste receptors (T2Rs) in the human airway detect harmful compounds, including secreted bacterial products. Here, using human primary sinonasal air-liquid interface cultures and tissue explants, we determined that activation of a subset of airway T2Rs expressed in nasal solitary chemosensory cells activates a calcium wave that propagates through gap junctions to the surrounding respiratory epithelial cells. The T2R-dependent calcium wave stimulated robust secretion of antimicrobial peptides into the mucus that was capable of killing a variety of respiratory pathogens. Furthermore, sweet taste receptor (T1R2/3) activation suppressed T2R-mediated antimicrobial peptide secretion, suggesting that T1R2/3-mediated inhibition of T2Rs prevents full antimicrobial peptide release during times of relative health. In contrast, during acute bacterial infection, T1R2/3 is likely deactivated in response to bacterial consumption of airway surface liquid glucose, alleviating T2R inhibition and resulting in antimicrobial peptide secretion. We found that patients with chronic rhinosinusitis have elevated glucose concentrations in their nasal secretions, and other reports have shown that patients with hyperglycemia likewise have elevated nasal glucose levels. These data suggest that increased glucose in respiratory secretions in pathologic states, such as chronic rhinosinusitis or hyperglycemia, promotes tonic activation of T1R2/3 and suppresses T2R-mediated innate defense. Furthermore, targeting T1R2/3-dependent suppression of T2Rs may have therapeutic potential for upper respiratory tract infections.

The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery

The bitter taste receptor T2R38 was recently described to play a role in upper airway innate mucosal defense. When activated by bacterial quorum‐sensing molecules, T2R38 stimulates the ciliated epithelial cells to produce nitric oxide (NO), resulting in bactericidal activity and an increase in mucociliary clearance (MCC). Polymorphisms within the T2R38 gene (TAS2R38) confer variability in activation of the receptor yielding dramatic differences in upper airway defensive responses (NO production and accelerated MCC) to microbial stimulation based on genotype. Our objective was to determine whether the nonprotective TAS2R38 polymorphisms, which render the receptor inactive, correlate with medically recalcitrant chronic rhinosinusitis (CRS) necessitating surgical intervention in the context of known risk factors, and thus identify whether the TAS2R38 genotype is an independent risk factor for patients undergoing functional endoscopic sinus surgery (FESS).

Genetics of the taste receptor T2R38 correlates with chronic rhinosinusitis necessitating surgical intervention

We recently demonstrated the bitter taste receptor T2R38 upregulates sinonasal mucosal innate defense in response to gram‐negative quorum‐sensing molecules through increased nitric oxide production and mucociliary clearance. T2R38 was initially identified in the quest to understand the variability in bitter taste perception to the compound phenylthiocarbamide (PTC) and demonstrated to have polymorphisms generating diplotypes dividing people into PTC supertasters, heterozygotes (with variable PTC detection), and nontasters. We have further demonstrated that sinonasal epithelial cultures derived from supertasters significantly increase innate defenses in response to gram‐negative quorum‐sensing molecules compared with sinonasal cultures derived from heterozygotes and nontaster individuals. Based on this data, we hypothesize that supertasters are less likely to require sinus surgery compared with heterozygous or nontasters and that supertasters have improved surgical outcomes.

Endoscopic sinus surgery: evolution and technical innovations

Prior to the introduction of functional endoscopic sinus surgery, several surgeons had begun to use telescopes to perform surgical procedures in the nose and sinuses. However, the central concepts of functional endoscopic sinus surgery evolved primarily from Messerklingers endoscopic study of mucociliary clearance and endoscopic detailing of intranasal pathology. The popularity of a combination of endoscopic ethmoidectomy plus opening of secondarily involved sinuses grew rapidly during the latter part of the twentieth century, and endoscopic intranasal techniques began to expand to deal with pathology other than inflammation. We present a review of the evolution of knowledge regarding the pathogenesis of inflammatory sinus disease since that point in time, and of the impact that this has had on the management of inflammatory sinus disease. We also detail the technological advances that have allowed endoscopic intranasal techniques to expand and successfully treat other pathology, including skull base and orbital disease. In addition, we describe evolving technologies which may further influence development within this field.

Use of topical nasal therapies in the management of Chronic rhinosinusitis

To determine whether the use of topical nasal therapies with saline alone and in combination with antibiotics, antifungals, or corticosteroids is effective in the treatment of patients with chronic rhinosinusitis (CRS).

Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion

Mucociliary clearance (MCC) is the primary physical airway defense against inhaled pathogens and particulates. MCC depends on both proper fluid/mucus homeostasis and epithelial ciliary beating. Vasoactive intestinal peptide (VIP) is a neurotransmitter expressed in the sinonasal epithelium that is up‐regulated in allergy. However, the effects of VIP on human sinonasal physiology are unknown, as are VIPs interactions with histamine, a major regulator of allergic disease. We imaged ciliary beat frequency, mucociliary transport, apical Cl‐ permeability, and airway surface liquid (ASL) height in primary human sinonasal air‐liquid‐interface cultures to investigate the effects of VIP and histamine. VIP stimulated an increase in ciliary beat frequency (EC50 0.5 μM; maximal increase ~40% compared with control) and cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent and Na+K+2Cl‐ cotransporter‐dependent fluid secretion, all requiring cAMP/PKA signaling. Histamine activated Ca2+ signaling that increased ASL height but not ciliary beating. Low concentrations of VIP and histamine had synergistic effects on CFTR‐dependent fluid secretion, revealed by increased ASL heights. An up‐regulation of VIP in histamine‐driven allergic rhinitis would likely enhance mucosal fluid secretion and contribute to allergic rhinorrhea. Conversely, a loss of VIP‐activated secretion in patients with CF may impair mucociliary transport, contributing to increased incidences of sinonasal infections and rhinosinusitis.—Lee, R. J., Chen, B., Doghramji, L., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Cohen, N. A., Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion. FASEB J. 27, 5094–5103 (2013). www.fasebj.org

TAS2R38 genotype predicts surgical outcome in nonpolypoid chronic rhinosinusitis.

Over 550,000 sinus surgeries are performed annually in the United States on patients with chronic rhinosinusitis (CRS). Although the results of sinus surgery vary widely, no known genetic factor has been identified to predict surgical outcomes. The bitter taste receptor T2R38 has recently been demonstrated to regulate upper airway innate defense and may affect patient responses to therapy. Our goal was to determine whether TAS2R38 genetics predicts outcomes in CRS patients following sinus surgery.

The effect of diabetes mellitus on chronic rhinosinusitis and sinus surgery outcome.

Patients with diabetes mellitus (DM) are known to be prone to infection. However, the association between diabetes and chronic rhinosinusitis (CRS) has not been well studied. We sought to determine the effects of DM on CRS culture results and quality of life (QOL) after functional endoscopic sinus surgery (FESS).