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.