Elevated Expression of RGS2 May Underlie Reduced Olfaction in COVID-19 Patients

Introduction

Deficiency or complete loss of smell (anosmia) is common in COVID-19, affecting a substantial number of patients and sometimes lasting for weeks or months following recovery [1,2]. Anosmia in COVID-19 patients was suggested as predictor for post-COVID19 fatigue syndrome (“long COVID”; [3]) and observed as a comorbidity with persistent post-COVID inflammation [4]. The biological pathways underlying olfactory deficiency in COVID-19 remain unclear. Albeit SARS-CoV-2 may enter the brain [5,6], it does not seem to be capable of infecting olfactory neurons [7]. It was recently shown that SARS-CoV-2 infection causes downregulation of olfactory receptors in olfactory neurons, which may explain COVID-19 related anosmia [8]. We hypothesize that the olfactory dysfunction in COVID-19 may additionally reflect an infection-driven upregulation of RGS2 (regulator of G protein signaling 2), a key regulator of nasal cavity G protein-coupled odorant receptors, whose signaling is diminished by the RGS2 protein [9]. RGS2 is known to be co-expressed with odorant receptors, and injection of RGS2 antibody into olfactory neurons was shown to enhance calcium currents in olfactory neurons stimulated with odorants [10].

Here, we present findings from analysis of RNA-sequencing data from nasopharyngeal samples, which show higher RGS2 mRNA levels in COVID-19 patients. While the biological pathways upregulating RGS2 mRNA in SARS-CoV-2 positive nasal tissues remain to be established, we present evidence that this is a consequence of the acute inflammation caused early in the span of infection. We present additional evidence for a correlation for higher RGS2 expression in populations with increased risk of COVID-19-induced anosmia.

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