Olfactory mucosa repair and defense: neuro-immune mechanisms and therapy

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Project summary: The olfactory epithelium is situated in the nasal passages at the interface with the environment – a location that makes it vulnerable to damage by both infectious and non-microbial threats. While the innate immune defenses of the respiratory epithelium are increasingly well understood, the immune mechanisms protecting the delicate olfactory neuroepithelium have not been fully elucidated. Inflammation of the olfactory epithelium can result in the loss of the sense of smell, which is a debilitating health problem in the United States significantly impacting the quality of life of affected individuals. The current COVID-19 pandemic has highlighted how viral infection and the local immune response of the olfactory epithelium can impair sense of smell function, although the mechanism is unknown. We hypothesize that the lining cells of the olfactory epithelium, called sustentacular cells, play a critical role protecting the underlying neurons by maintaining a strong physical barrier and providing a supporting framework. Once damaged, olfactory tissue has a remarkable and unique neuroregenerative capacity, allowing rapid repair by creation of new neurons. The signals that drive and regulate regeneration by olfactory progenitor cells are unclear. Our preliminary studies in mice reveal that regulated inflammation is important to initiating normal repair after olfactory injury. We also have found that olfactory stem cells deep in the mucosa are capable of communicating with immune cells to mediate inflammation. In this way, we propose that olfactory stem cells provide innate immune protection to the epithelium. We hypothesize that injury to the surface barrier exposes olfactory stem cells to stimuli that drive inflammation and replacement of apical cells. The overall goal of this proposal is to explore neuroepithelial-immune interactions in the olfactory epithelium. In aim 1, we will investigate the innate immune activity of olfactory stem cells and demonstrate whether inflammatory cells and their chemical signals modulate basal cell function. In aim 2, we will explore the role of stem cells in modulating the immune response and in fighting infection. Finally, in aim 3, we will study the immune response of sustentacular cells and olfactory stem cells to inflammatory signals related to two common causes of loss of the sense of smell: nasal polyps and infection with SARS-CoV-2. These studies will significantly advance current knowledge about the olfactory system and create an opportunity to develop innovative therapies for important health conditions impacting the sense of smell.