The Blood Olfactory Barrier and Consequences of Neurotropic Viral Infection in the Olfactory System

Abstract

The olfactory mucosa conducts the sense of smell, an integral way we connect to our external environment. As part of the upper respiratory tract, the olfactory mucosa (OM) is a barrier to the outside world, but also forms a direct connection to the brain via the olfactory sensory neuron (OSN). The olfactory sensory neurons in the epithelial surface detect airway odorant molecules and send their axon tracts that form cranial nerve I directly into the olfactory bulb. Unlike other highly neuronal tissue, the olfactory mucosa is vulnerable to the external environment and airborne pathogens. Thus, there must be ways to defend this barrier surface to prevent tissue damage and subsequent smell loss. Furthermore, critically, infection of the olfactory mucosa and olfactory sensory neurons can lead to pathogen spread into the brain. Therefore, robust host defenses are needed to protect from neuroinvasion. The purpose of this dissertation is to highlight the consequences of olfactory neurotropic viral infection. Additionally, in this dissertation I provide the first characterization of specialized endothelial cells in the olfactory mucosa that form the blood-olfactory barrier. In chapter one, I describe the anatomy of the olfactory mucosa. I then detail vulnerabilities of the olfactory mucosa to pathogens and inflammatory disorders that can result in lasting consequences including smell loss. I also cover the stromal defenses and innate and adaptive immune responses that have been studied in the olfactory mucosa. In chapter two, I investigate how the host responds to viral infection in the olfactory mucosa to balance tissue repair and olfaction with immune defense using the model of vesicular stomatitis virus infection. In chapter three, I characterize a previously undescribed barrier in the olfactory mucosa, termed the blood-olfactory barrier (BOB). Like the blood-brain barrier in the central nervous system, the blood endothelial cells in the olfactory mucosa restrict nonspecific passage of blood borne proteins and harbor features of highly specialized endothelial cells akin to those found in the brain. Finally in chapter four, I study a newly described consequence of viral infection in the brain. I find that antiviral CD8+ T cells form fusion cells with brain resident astrocytes. I use adoptive transfer and genetic lineage tracing via histology in two viral infection systems in mice to study these fusion events. This dissertation highlights the importance of the olfactory system as a brain barrier and how neurotropic infections can have lasting consequences, opening novel avenues for future investigation in the field of olfactory immunology.