COVID-19 Anosmia: High Prevalence, Plural Neuropathogenic Mechanisms, and Scarce Neurotropism of SARS-CoV-2?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). It is known as a respiratory virus, but SARS-CoV-2 appears equally, or even more, infectious for the olfactory epithelium (OE) than for the respiratory epithelium in the nasal cavity. In light of the small area of the OE relative to the respiratory epithelium, the high prevalence of olfactory dysfunctions (ODs) in COVID-19 has been bewildering and has attracted much attention. This review aims to first examine the cytological and molecular biological characteristics of the OE, especially the microvillous apical surfaces of sustentacular cells and the abundant SARS-CoV-2 receptor molecules thereof, that may underlie the high susceptibility of this neuroepithelium to SARS-CoV-2 infection and damages. The possibility of SARS-CoV-2 neurotropism, or the lack of it, is then analyzed with regard to the expression of the receptor (angiotensin-converting enzyme 2) or priming protease (transmembrane serine protease 2), and cellular targets of infection. Neuropathology of COVID-19 in the OE, olfactory bulb, and other related neural structures are also reviewed. Toward the end, we present our perspectives regarding possible mechanisms of SARS-CoV-2 neuropathogenesis and ODs, in the absence of substantial viral infection of neurons. Plausible causes for persistent ODs in some COVID-19 convalescents are also examined.