Marco Tizzano, Ph.D. - US grants

Project Summary Harmful compounds and xenobiotics carried in inhaled air continually assault the nasal cavity and can cause severe nasal inflammation. Worldwide, hundreds of millions of adults and children suffer with asthma, rhinosinusitis, and other respiratory conditions. Environmental irritants and bacterial infections can trigger these types of nasal inflammation. In the nasal passages, the detection of inflammation triggers is mostly mediated by the trigeminal chemosensory system and the solitary chemosensory cells (SCCs). Known ligands of the SCCs are the bitter compound denatonium benzoate, used in several household products, and acyl homoserine lactones (AHLs) generated by bacterial infections. SCCs, which express elements of the bitter taste (T2R) transduction cascade, are innervated by trigeminal nerve fibers, which relay their responses to the central nervous system, triggering release of neuropeptides into the mucosa, evoking inflammatory/immune responses and respiratory-protective reflexes to eliminate the irritating compounds. Denatonium and AHLs are prototypical compounds for the activation of the T2R pathway in SCCs. Thus, studying their effects on SCCs can increase our understanding of airway chemoreception and of long-term effects of exposure to SCC triggers. In this proposed research, we will determine whether SCC activation by denatonium and bacterial AHLs triggers avoidance behavior, preventing further inhalation of these irritants (Aim 1); whether the presence of denatonium triggers the same nasal inflammation and immune response as bacterial infections (Aim 2); and whether forced exposure to denatonium or AHLs can damage the olfactory epithelium and if SCCs are protective in these circumstances (Aim 3). Because social, work, and other situations often require people to ignore physiological warnings triggered by SCCs and stay in environments where irritating and toxic compounds are present, it is important to understand how SCCs function and to determine the chemosensory mechanisms and the physiological/behavioral effects of commonly encountered irritant compounds like denatonium. Understanding the transduction cascades and mechanisms involved in these responses will offer new selective pharmacological targets for several airway pathologies.

Project Summary Periodontal disease, which results from bacterial infection and inflammation of the gums and bone that surround and support the teeth, affects nearly half of US adults over 30, with ~9% having severe periodontitis. The hallmark of periodontitis is destruction of alveolar bone, resulting ultimately in extended tooth loss and oral disability. Periodontitis is a major oral health problem, particularly among the elderly, that increases the risk for systemic diseases, including atherosclerosis, rheumatoid arthritis, and diabetes mellitus. The general goals of this grant are to determine the role of newly discovered gingival solitary chemosensory cells (gSCCs) in protecting against periodontitis, to identify the receptors, signaling pathways and effectors involved in innate immunity evoked by gSCC activation, and to identify compounds that activate gSCCs to harness host innate immunity to reduce periodontitis. Periodontitis results from polymicrobial dysbiosis, which perturbs the ecologically balanced oral microbiota, and from disruption of the host innate immunity, which also contributes to the destruction of periodontal tissue. While much is known about how microbes and host immunity contribute to periodontitis, it is still unclear which gingival cells protect against the disease. Recent studies in several types of mucosae have identified taste cell-like SCCs as specialized chemosensitive sentinel cells that detect bacteria and evoke host innate immune responses. Most recently, we have identified gSCCs in the mouse gingival junctional epithelium that is part of the epithelial barrier protecting against bacterial infection of the tooth and surrounding gingiva. gSCCs express bitter taste receptors along with other taste transduction components, respond to bacterial signaling molecules, and trigger intrinsic innate immunity to protect against periodontitis. The experiments of this proposal study the role of gSCCs in gingival/tooth health to determine if gSCCs evoke innate immune responses that prevent overgrowth of oral bacteria in the gingival mucosa (Aim 1); identify the receptors and signaling components of gSCCs and the mechanism by which gSCCs promote gingival release of antimicrobial peptides and inflammatory cytokines (Aim 2); and determine if ?on demand ?activation of the gSCC signaling pathway reduces periodontitis (Aim 3). Understanding the initiating receptors and underlying mechanisms of these responses may lead to new approaches to promote oral health and treat periodontitis.