Taste dysfunction in Long COVID

Abstract

Persistent taste dysfunction may occur both as acute and long-term symptoms of SARS-CoV-2 infection (Long COVID), yet the underlying mechanisms are unknown at the histological, cellular, and molecular levels. This study investigates the underlying pathology in 28 non-hospitalized subjects who reported persistent taste disturbances for over 12 months after testing positive for SARS-CoV-2. To assess taste function, subjects completed the Waterless Empirical Taste Test (WETT), which quantifies the subject's ability to taste each of the five human taste qualities: sweet, umami, bitter, sour, and salty. Biopsies of fungiform papillae were collected from 20 participants and analyzed histologically for overall taste bud structure and innervation and by quantitative PCR (qPCR) for expression of markers for different taste receptor cells (TRCs). Although all subjects reported subjective taste dysfunction, only five scored below the 20th percentile on overall taste sensitivity. However, 12 subjects exhibited total loss of one or more taste qualities and another 13 subjects tested below the 95% confidence interval for at least one taste modality. Notably, loss of sweet, umami, or bitter tastes -- qualities mediated by a PLCβ2-transduction cascade -- was significantly more common than loss of sour and salty, and this loss correlated with reduced expression of PLCβ2 mRNA. Histological analysis revealed generally preserved taste bud structure and innervation in all cases, with occasional disorganization resulting in isolated PLCβ2-immunoreactive cells. Our findings suggest long-term taste dysfunction after COVID-19 disproportionately impacts PLCβ2-dependent taste qualities and is not due to widespread structural damage of the taste periphery.

Figure 1:

A) The mRNA levels for PLCß2 (r(18)=.48, p= .03) and TAS1R3(r(18)=.49, p= .03) correlate with the overall taste ability of each subject. B) The mRNA level for TAS1R3 correlates with the combined taste score for the related taste qualities (Sweet and brothy) (r(18)=.51, p= .02).

Figure 2:

Appearance of normal taste buds sectioned in different planes from different subjects. Red = PLCß2 immunoreactivity showing Type II taste cells; Green = TUJ1 immunoreactivity for nerve fibers. Typical taste buds have more than one PLCß2+ cell surrounded by a dense network of TUJ1-stained nerve fibers. Green profiles outside of taste buds are extragemmal nerve fibers typical of lingual epithelium (Moayedi, Michlig et al. 2021). a, b. Taste buds sectioned longitudinally appear similar in shape to garlic bulbs or onions (from Subject (SWE) 15. c) Taste buds sectioned perpendicular to their long axis appear circular (from subject (SWE) 29 who reported a total absence of taste perception (taste score of 13, showing no correct responses to any tastant). Scale bar in panel (b) applies to all panels.

Figure 3:

Examples of abnormal PLCß2+ taste-like cells from 4 cases. (A & B). Subject (SWE) 12 had a taste score of 35 (54%). (C) From subject (SWE) 13 who had a score of 22 (21%). In both cases (A & C), innervated PLCß2+ (red arrows) cells occur in relative isolation within the epithelium. Innervation of these cells (green: TUJ1) is sparse unlike innervation of taste buds (cf Fig. 2). These cells may represent very small taste buds or simply PLCß2+ cells lying outside of a taste bud structure. Panel B shows a higher magnification of one such isolated PLCß2+ cell and its innervation stained for the presence of P2X3, a neural receptor predominantly on nerve fibers that innervate taste buds. Panels D-E are from case (SWE) 24 with a taste score of 17 (4%) showing examples of aberrant PLCß2+ cells (red arrows) outside of a taste bud structure. Panel F: A disorganized taste bud from case SWE 29 who reported a total absence of taste perception (taste score of 13, showing no correct responses to any tastant). The heavy innervation is typical of taste buds, but the cellular structure revealed by PLC-staining (red) does not show typical taste bud organization.