The Molecular Basis of Olfactory Dysfunction in COVID-19 and Long COVID

Olfactory dysfunction (OD) is not uncommon following viral infection. Herein, we explore the interplay of host genetics with viral correlates in coronavirus disease 2019 (COVID-19)- and long COVID-related OD, and its diagnosis and treatment that remain challenging. Two genes associated with olfaction, UGT2A1 and UGT2A2, appear to be involved in COVID-19-related anosmia, a hallmark symptom of acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly in the early stages of the pandemic. SARS-CoV-2 infects olfactory support cells, sustentacular and Bowman gland cells, that surround olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) where the initial step of odor detection takes place. Anosmia primarily arises from the infection of support cells of the OE, followed by the deciliation and disruption of OE integrity, typically without OSN infection. Through the projected axons of OSNs, the virus could theoretically reach the olfactory bulb and brain, but current evidence points against this route. Intriguingly, SARS-CoV-2 infection of support cells leads to profound alterations in the nuclear architecture of OSNs, leading to the downregulation of odorant receptor-related genes, e.g., of Adcy3. Viral factors associated with the development of OD include spike protein aminoacidic changes, e.g., D614G, the first substitution that was selected early during SARS-CoV-2 evolution. More recent variants of the Omicron family are less likely to cause OD compared to Delta or Alpha, although OD has been associated with a milder disease course. OD is one of the most prevalent post-acute neurologic symptoms of SARS-CoV-2 infection. The tens of millions of people worldwide who have lingering problems with OD wait eagerly for effective new treatments that will restore their sense of smell which adds value to their quality of life.