Immune Barriers in the Olfactory Mucosa

Abstract

The olfactory mucosa is a unique tissue because it directly connects the outside world to the central nervous system (CNS). From the apical side of the olfactory epithelium, olfactory sensory neurons (OSNs) extend their cilia directly into the airway. Simultaneously, their axons tunnel basolaterally through the skull and directly into the olfactory bulb of the brain. OSNs therefore serve as a single-cell bridge from the nasal airway to the CNS. The olfactory mucosa can therefore be considered an important mucosal barrier in two regards: it forms a component of the upper respiratory tract to defend against airborne pathogens, but it also must defend the brain from neurotropic microbes. At the same time, the olfactory mucosa must balance immune defense with tissue homeostasis and neuronal function to preserve the sense of smell. Despite these important roles, all of which relate to the immune system, the immune cells in this tissue have been woefully understudied. The purpose of this dissertation work is to characterize the immune barriers within the olfactory mucosa. This includes the first comprehensive characterization of hematopoietic cells in the olfactory mucosa, but also includes the first description of some important structural and stromal immune barriers in the tissue. The first chapter of this dissertation will review the plethora of olfactotropic pathogens, both neurotropic and otherwise, that impact the olfactory mucosa. Next, I will detail the methods I have developed to study and isolate tissue-resident immune cells of the olfactory mucosa. The third chapter will focus on the roles of macrophages in the olfactory tissue, describing for the first time two distinct subsets that contribute to neuronal maintenance and immune defense. The fourth chapter will highlight two important discoveries related to humoral defense of the olfactory mucosa. We describe for the first time the blood-olfactory barrier and mucosal plasma cells in the olfactory mucosa. Lastly, I will conclude by contextualizing these findings within the broader literature of upper airway immunity, giving the first encompassing review of olfactory immunity. Combined, the work in this dissertation will form an important building block for the field of olfactory immunology.