Anosmia-hyposmia and dysgeusia in COVID-19 may be due to SARS-CoV-2 protein mimicry of olfactory receptors*

Background: Anosmia-hyposmia and dysgeusia are common symptoms of mild-to-moderate COVID-19 cases. They are usually, but not always, reversible and the cause is unknown. Methodology: Proteonomic similarity searching (BLAST) was used to test whether SARS-CoV-2 has an unusual degree of similarity to human olfactory receptors as compared with other viruses. Results: SARS-CoV-2 displays two orders of magnitude more similarities to human olfactory receptors than does any other upper respiratory virus or rhinovirus and five times as many similarities as cold-causing coronaviruses. Conclusions: It is hypothesized that IgA antibodies produced against SARS-CoV-2 proteins and secreted in saliva and mucus bind to and block human olfactory receptors. These antibodies cause the reversible form of anosmia-hyposmia associated with COVID-19 infection. The mimicry may also, rarely, lead to autoimmune disease against neurons expressing olfactory receptors, in which case oral or nasal steroids may be therapeutic.


Introduction
Loss of smell and taste (anosmia or hyposmia) and/or taste (dysgeusia) are now recognized to be significant, often presenting, clinical features of mild-to-moderate SARS-CoV-2 infection affecting, on average, more than 50% of patients (range 5 to 98% in different studies) with a preponderance in women (ca. 70%) and individuals under the age of 50 (e.g., (1,2) ). Various hypotheses have been proffered to explain the loss of olfactory receptor function including direct infection of olfactory neurons; infection of sustentacular (neuronal support) cells resulting in loss of olfactory receptor-containing cilia; and local inflammation of the olfactory epithelium (reviewed in (3) ) but no definitive explanation yet exists. Evidence is presented here that SARS-CoV-2 proteins exhibit multiple sequences that mimic highly conserved extracellular loop and binding regions of human olfactory proteins. It is hypothesized that these SARS-CoV-2 antigens induce immunoglobulin type A (IgA), that is released into saliva, mucus and tears to control the infection but which also bind to and block olfactory receptors.

Materials and methods
BLASTP (version 2.2.31+) on the www.expasy.org website was used to search for possible similarities between the entire sequences of SARS-CoV-2 proteins and human olfactory receptors with the following settings: BLOSUM80 was used to identify short sequences such as those presented by human leukocyte antigens and recognized by T cell receptors; gaps disallowed; low complexity regions screened out; E set to 1000 with 3000 best matches displayed. All SARS-CoV-2 proteins were tested along with those of coronavirus HKU1, SARS-CoV-1, Middle East Respiratory Syndrome virus (MERS), and seventeen control virus proteomes including multiple rhinoviruses associated with anosmia (4) (Table 1). Results were further screened by identifying the location of the match on the presumed 3D structure of olfactory receptors as provided in the UniProt accession data ( Figure 1). Statistics were not run since the results are so intrinsically obvious. CoV-1 and MERS, which were also characterized by anosmia/ hyposmia (4) . This highly conserved mimicry would assure broad loss of olfaction. It is unlikely that cytoplasmic regions of similarity ( Figure 1) are accessible to antibodies though they might become so during autoimmune disease.

SARS
The vast majority of the sequence similarities between SARS-CoV-2 proteins and olfactory receptors (and all of those shown in Figure 1) satisfy the criterion that at least six of the amino acids in a sequence of ten are identical (where a pair of acceptable substitutions counts as one identity), making them excellent candidates for antigenic cross-reactivity as determined previously by experiment (5) .

Discussion
Infection with SARS-CoV-2 elicits early, high titers of immunoglobulin type A (IgA) antibodies that rapidly decrease after the virus is eliminated with a titer half-life of about ten days (6) . These IgA antibodies are the primary means of virus neutralization in mucosa (7) . I propose the novel hypothesis that IgA cross-react with olfactory receptors blocking receptor function without killing the associated neurons. The better the immune response, the more complete the anosmia but, correspondingly, the better-controlled the infection. This hypothesis explains why gustatory and olfactory impairment are associated with mild to moderate COVID-19 symptoms (1,2) and why most patients recover smell and taste within four weeks as the virus is cleared from the body and IgA antibody levels decrease (6,7) . The hypothesis is testable by examining the saliva of anosmic, hyposmic or dygeustic COVID-19 patients for IgA antibodies that bind to A corollary to the hypothesis could explain why some COVID-19 patients (as many as 25%) develop chronic anosmia or hyposmia that does not resolve even after three or more months (8) . Such patients may develop an autoimmune disease against their olfactory neurons triggered by the molecular mimicry illustrated in Figure 1 between SARS-CoV-2 proteins and olfactory receptors. While molecular mimicry is often associated with induction of autoimmune diseases, however, it is generally considered to be insufficient to trigger disease (9) . Current theory suggests that molecular mimicry requires an associated bystander or complementary infection that prevents T-cell tolerization needed to protect "self" cells (9) . Patients experiencing chronic smell and taste loss may therefore differ from those with transient symptoms in having evidence of a viral or bacterial co-infection along with SARS-CoV-2. Such patients should be tested for complementactivating autoantibodies with specificity to olfactory receptors and loss of T-cell tolerance to olfactory neurons.
Nasal or oral steroids might be useful in treating the autoimmune form of the disease after a patient has repeatedly tested negative for SARS-CoV-2 but are contraindicated during active infection and in cases of transient smell and taste loss because of interference with active immunity against SARS-CoV-2 (8) .

Conclusions
In sum, it is demonstrated that SARS-CoV-2 shares significant similarities with a huge number of human olfactory receptors and it is proposed that IgA antibody produced in response to the viral infection then blocks these receptors. This explains