Olfactory immunology: the missing piece in airway and CNS defence

Abstract

The olfactory mucosa is a component of the nasal airway that mediates the sense of smell. Recent studies point to an important role for the olfactory mucosa as a barrier to both respiratory pathogens and to neuroinvasive pathogens that hijack the olfactory nerve and invade the CNS. In particular, the COVID-19 pandemic has demonstrated that the olfactory mucosa is an integral part of a heterogeneous nasal mucosal barrier critical to upper airway immunity. However, our insufficient knowledge of olfactory mucosal immunity hinders attempts to protect this tissue from infection and other diseases. This Review summarizes the state of olfactory immunology by highlighting the unique immunologically relevant anatomy of the olfactory mucosa, describing what is known of olfactory immune cells, and considering the impact of common infectious diseases and inflammatory disorders at this site. We will offer our perspective on the future of the field and the many unresolved questions pertaining to olfactory immunity.

Fig. 1 |. Heterogeneity of the upper respiratory tract: the olfaction fraction.

a, The upper respiratory tract consists of two distinct tissues with important implications for immunity, namely the olfactory mucosa (blue) and the respiratory mucosa (beige). The olfactory mucosa must balance olfaction with immune defence and acts as a barrier to the CNS. The olfactory and respiratory mucosae have different requirements for immune protection, including local humoral protection from resident plasma cells in the olfactory mucosa. b, Prior studies of intranasal infection and immunity often indicate that upon rechallenge with a pathogen, pathogen replication is reduced. However, these studies treat the nasal passages as a homogeneous tissue. In actual fact, the overall reduced pathogen replication that is observed could represent many different scenarios depending on the tropism of the pathogens used and the quality of the immune response they induce. The lower panel indicates some hypothetical examples, considering whether a pathogen shows tropism for the olfactory mucosa (OM) alone, the respiratory mucosa (RM) alone or for both the olfactory mucosa and respiratory mucosa. Differences between the olfactory mucosa and respiratory mucosa, both in pathogen tropism and protective immune parameters, must be carefully considered and analysed to yield interpretable data regarding consequences of infection or immunization.

Fig. 2 |. Cell types and effector mechanisms in the olfactory mucosa.

a, The figure indicates the parenchymal cell types that compose the olfactory mucosa. The luminal side is coated in mucus and directly exposed to the airway. The neuroepithelium contains olfactory sensory neurons (OSN), sustentacular cells, microvillar cells and the Bowman’s glands. Lining the basal lamina are horizontal basal stem cells (HBCs) and globose basal stem cells (GBCs). Within the lamina propria, OSN axon tracts run directly towards the olfactory bulb of the brain. Olfactory ensheathing cells (OECs) are interwoven within these axon bundles. Also, within the lamina propria are lymphatic and blood endothelial cells. The blood–olfactory barrier (BOB) prevents antibodies and other large circulating molecules from entering the olfactory mucosa. The exact composition of the BOB is unknown; beyond endothelial cells, pericytes, macrophages or olfactory ensheathing cells could contribute to barrier integrity. b, Innate immune cells of the olfactory mucosa are indicated in dark red. At homoeostasis, macrophages can be observed within the neuroepithelium and lamina propria with several distinct morphologies. During inflammation, dendritic cells (DCs), neutrophils, monocytes and eosinophils can infiltrate the tissue and contribute to the immune response. c, Following infection or immunization, T cells and B lineage cells migrate to the olfactory mucosa and take up long-term residence. These lymphocytes (shown in purple) can provide protective local immunity against future challenge. d, Intracellular olfactotropic pathogens can be neuroinvasive or non-neuroinvasive. Viruses and bacteria may infect non-neuronal epithelial cells or OSNs. Neurotropic pathogens that infect OSNs may either be cleared before reaching the CNS or migrate through OSN axons into the olfactory bulb. Extracellular pathogens, such as bacteria and eukaryotes, can migrate along axon bundles to reach the brain. These pathogens are better able to infect the olfactory mucosa when the tissue has been previously damaged, compromising existing structural impediments. IFN, interferon; iNOS, inducible nitric oxide synthase; OM, olfactory mucosa; TNF, tumour necrosis factor.