The nasal respiratory epithelium contains thousands of specialized chemoreceptor cells (solitary chemosensory cells) that form functional contacts with the trigeminal nerve. Activation of the trigeminal nerve either directly by irritants or through the agency of these cells evokes protective airway reflexes such as sneezing, coughing or apnea. The proposed experiments investigate the role of these solitary chemosensory cells in the detection of quorum sensing molecules secreted by pathogenic bacteria as they transition from being benign to the virulent state. Our preliminary data show that the cells and the trigeminal system at large can respond to bacterial signaling molecules. The experiments in this proposal will examine the chemical specificity of the response, test the transduction cascade and possible role of T2R (bitter taste) receptor molecules, and finally examine the effects on the surrounding epithelium and the trigeminal sensory nerve fibers of activation of the chemosensory cells. In order to assess the effectiveness of various bacterial signaling molecules, we will use two bioassay systems: i) respiratory reflexes evoked by application of the compound to the nasal epithelium in a semi-intact preparation, and ii) Ca ++ -imaging of chemosensory cells isolated from the epithelium of transgenic mice in which GFP marks the relevant cell population. We will use the same preparations to assess the potential role of T2R receptors and the associated PLC-signal cascade. Specific blockers of PLC- signalling should disrupt transduction and eliminate the Ca ++ signal if the T2R/PLC pathway is necessary. Similarly, respiratory depression should be lessened in both TRPM5 and gustducin-knockout animals if these elements are crucial for the transduction of bacterial signals. Finally, we will assess whether activation of the chemosensory cells secondarily causes changes in the surrounding epithelium - either via release of paracrine mediators (e.g. ATP, acetyl choline) or through the agency of activation of the peptidergic nerve fibers that innervate the epithelium. Taken together, these experiments will determine the mechanisms used by solitary chemosensory cell to detect the bacterial signaling molecules and whether the cells are instrumental in provoking a local tissue and/or immune response to the potential pathogens.

Public Health Relevance

The proposed research will investigate a newly discovered nasal chemosensory system that detects molecules that regulate the virulence of pathogenic bacteria. This research is designed to test the possible role of these sensors in a first line of tissue defense against bacterial nasal and upper respiratory infections.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009820-04
Application #
8299613
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$446,124
Indirect Cost
$150,101
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Tizzano, Marco; Finger, Thomas E (2013) Chemosensors in the nose: guardians of the airways. Physiology (Bethesda) 28:51-60
Barham, Henry P; Cooper, Sarah E; Anderson, Catherine B et al. (2013) Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa. Int Forum Allergy Rhinol 3:450-7
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Tizzano, Marco; Cristofoletti, Mirko; Sbarbati, Andrea et al. (2011) Expression of taste receptors in solitary chemosensory cells of rodent airways. BMC Pulm Med 11:3
Tizzano, Marco; Gulbransen, Brian D; Vandenbeuch, Aurelie et al. (2010) Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A 107:3210-5