Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“

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A6-Subproject

Pathogen recognition by taste receptors and coupling to mucociliary clearance (Krasteva-Christ / Kummer)

 

Quorum sensing molecules (QSM) and other bacterial products act as agonists on canonical bitter taste receptors (Tas2R family) of oropharyngeal taste buds, thereby evoking the sensation of bitterness. It has recently been demonstrated by others and us that this canonical bitter taste transduction cascade is also expressed by upper airway and tracheal solitary chemosensory (“brush”) cells which enables them to respond to synthetic bitter substances and to Pseudomonas aeruginosa acyl homoserine lactone QSM. Upon stimulation, these cells release acetylcholine to excite sensory nerve fibres, thereby eliciting aversive respiratory reflexes. Acetylcholine is also a powerful activator of mucociliary clearance, a major innate defense mechanism of the airways. Sugars (sweet) and free amino acids (umami), Tas1R ligands, also represent potential harmful substances on the mucosal surface since they are nutrients for several pathogenic bacteria, promote their growth, and also may be secretory products (poly-L-glutamate is a constituent of biofilms). Based upon our previous work, we here raise the hypothesis that airway epithelial cells utilize canonical taste receptors (Tas1R and Tas2R families) for pathogen recognition and, upon stimulation, either directly respond in a cell-autonomous manner or modulate mucociliary clearance by paracrine release of acetylcholine or ATP. Specifically, we aim to 1) identify functionally active taste receptors in specified airway epithelial cells (e.g. brush cells, ciliated cells, neuroendocrine cells), 2) elucidate paracrine signalling pathways coupling sensing to ciliary activity, and 3) elucidate the consequences of disturbed mucosal taste transduction for bacterial colonization and severity of infection. This will be addressed in isolated pure cell preparations (#1 receptor repertoire and sensing mechanisms), isolated airways (#2 coupling to ciliary activity), and in vivo mouse models, including generation of mice selectively lacking brush cells in the respiratory epithelium, utilizing the expertise of the consortium in bacterial infection models (#3). We expect new mechanistic insight into the role of taste receptors in pathogen recognition and defense, which may offer new therapeutic strategies to combat airway and pulmonary infection.