Chemosensory Dysfunction in COVID-19: Integration of Genetic and Epidemiological Data Points to D614G Spike Protein Variant as a Contributing Factor

Abstract

After several months of rapid pandemic expansion, it is now apparent that the SARS-CoV-2 coronavirus interferes with smell and taste sensation in a substantial proportion of COVID-19 patients. Recent epidemiological data documented intriguing differences in prevalence of chemosensory dysfunctions between different world regions. Viral genetic factors as well as host genetic factors appear to be relevant; however, it is not yet known which mutations or polymorphisms actually contribute to such phenotypic differences between populations. Here, we discuss recent genetic and epidemiological data on the D614G spike protein variant and assess whether current evidence is consistent with the notion that this single nucleotide polymorphism augments chemosensory impairments in COVID-19 patients. We hypothesize that this spike variant is an important viral genetic factor that facilitates infection of chemosensory epithelia, possibly acting together with yet to be identified host factors, and thereby increases smell and taste impairment. We suggest that the prevalence of chemosensory deficits may reflect the pandemic potential for transmissibility and spread which differs between populations.

Keywords: ACE2; COVID-19; Chemosensory dysfunction; D614G mutation; D614G variant; olfactory dysfunction.

Figure 1

Schematic representation of the key role of the coronavirus spike protein-RBD binding efficiency to human ACE2 in the development of olfactory dysfunction. NL63, SARS-CoV-1, and SARS-CoV-2 are three human coronaviruses that use hACE2 to enter host cells. The RBD of spike proteins in NL63 and SARS-CoV-1 have lower affinity to hACE2 as compared to SARS-CoV-2. The D614G substitution, even though it is not located within the RBD (so it will not change the affinity of pure RBD to hACE2), changes the interprotomer spike energetics and enhances RBD exposure, thus favoring the likelihood of binding of the G614-spike protein to hACE2 as compared with the D614 variant. Convincing alternative explanations have also been proposed, indicating that G614 results in spike protein stabilization and increased spike protein incorporation into pseudovirions, thus creating more ACE2-binding sites on the virion surface. We propose that hyposmia and anosmia require virus binding in the olfactory epithelium above a certain threshold, and for this reason chemosensory dysfunctions did not occur with infections of the SARS-CoV-1 or NL63 viruses. Thresholds and binding efficiencies are approximations based on the literature for different cell lines and are not yet known for cells in the olfactory epithelium. RBD, receptor binding domain of the spike protein; hACE2, human ACE2 receptor, NL63, human coronavirus HCoV-NL63.