Sensory Homology: The Link between Taste and Smell in COVID-19

How does gustation work?

Gustation is the signal induced by the interaction of a chemical ‘tastant’ with a taste receptor on taste buds. Taste buds are mostly found on the tongue, but are also along the cheeks, soft palate, pharynx, epiglottis and other parts of the digestive tract. There are five established ‘tastes’: sweet, salty, bitter, sour, umami. Contrary to prior thought, different tastes are not perceived based on the organization of different taste receptors. All taste buds in the oral cavity express receptors for all of the 5 'tastes'. On the tongue, for instance, taste buds are on ridges called papillae. Each taste bud has around 100 specialized taste receptor epithelial cells. There are several types of epithelial cells in the taste bud, including gustatory cells, supporting cells and basal stem cells. The stem cells replenish the epithelium weekly since the tongue’s function encourages the sloughing off and turnover of cells. The gustatory cells, which sense tastants through chemoreceptors, are not neurons, unlike the OSNs in the olfactory epithelium. Tastants from food dissolve in saliva to diffuse into taste pores in order to bind to these receptors on gustatory cells. When the tastant binds to its receptor, the gustatory cells release neurotransmitters/ATP that can then activate the neurons in the facial, glossopharyngeal and vagus cranial nerves. Neurons fire action potentials to the gustatory nucleus in the medulla and the thalamus to eventually reach the gustatory cortex, where taste is perceived and digestive/endocrine signals are prompted.

The ‘taste’ transduced to the brain depends on how the action potential was triggered: if upon binding the tastant, for instance, triggered the opening of sodium channels, the tastant is interpreted as ‘salty’. If a sweet tastant were engineered to trigger a salty receptor, the brain would interpret the tastant as salty. Additionally, the gustatory nucleus also controls salivation indirectly by stimulating the hypothalamus and amygdala. In essence, taste and salivation, as you would expect, are interrelated. Maybe this rings a bell to Ivan Pavlov’s salivating dogs upon conditioning to a tasty treat.

How are smell and taste related?

Smell and taste are very interrelated so it is not surprising for both to be lost in COVID-19 patient pathology. Both smell and taste transduce sensory signals through chemoreceptors in taste bud gustatory cells and olfactory sensory neurons. Chemoreceptors detect endogenous or exogenous chemicals; in the case of olfaction, the chemicals detected are volatile. Other senses utilize photoreceptors (for sight) or mechanoreceptors (such as hair cells for hearing) to translate information from the environment into action potentials the brain can interpret. Having exposed, sensory neurons is biology’s way of linking the nervous system to the outside world.

The homology between the olfactory and gustatory epithelial tissues is astounding! Both epithelial tissues exhibit cilia on the apical surface that bind to odorants or tastants. Both have basal stem cells to routinely regenerate the tissue very rapidly, as the tissue is exposed and vulnerable to damage. Both have supporting cells to provide structural and metabolic support to the epithelium as well as nerves to transmit signals to the brain. What should not come as a shock is that these features are not all exclusive to these sensory epithelia; many are common to all epithelia in general.

Anatomically, the pharynx connects the oral and nasal cavity so that food odorants can

'land' on the olfactory epithelium, amplifying the sensory ‘taste’ experience. Smell fine tunes our perception of taste. Hence, when one loses their sense of smell, food doesn't taste as good, independently of gustation. Gustation alone is, in fact, limited in the sensory signals it communicates. Instead of recognizing 10,000 odorants, as in olfaction, gustation only interprets and groups tastants into 5 output signals. With gustation alone a certain dish may just ‘taste’ salty, for example, leaving no space for the nuances smell can distinguish that may make that salty dish ‘anchovies’. Evolutionarily, this underscores how unique smell is as a sensation: having more sensitivity and diversity of receptors is more adaptive in a survival context. All in all, the term taste is not gustation alone. Taste is the combination of olfaction and gustation.

Mechanisms of dysgeusia in COVID-19:

Loss of gustation is known as dysgeusia, a potential clinical biomarker of COVID-19 that tends to go hand in hand with anosmia (loss of smell). ACE-2, the portal of entry for CoV2, is enriched in a subpopulation of non-gustatory epithelial cells on the tongue, but not in the taste buds themselves. However, this does not necessarily mean gustation is not impacted by CoV2 infection. As in my previous post on anosmia, there may be inconsistencies when evaluating ACE-2 expression. ACE-2 inhibitors are known to trigger smell and gustation disorders, suggesting a potential mechanism for loss of taste in COVID-19.

Moreover, CoV2 RNA is present early in the saliva of patients, even before pulmonary lesions. Hypoxia (lack of oxygen) in later, more severe stages of COVID-19, is thought to be related to loss of gustation due to poor oxygen transport, however poor oxygen transport is detrimental to any tissue. Although this is not a specific mechanism, hypoxia may be related to delayed sensory regeneration of taste.

To what extent loss of taste in COVID-19 is due to pathology in the olfactory epithelium or to a mechanism in gustation is unknown. Much less is known about the underlying mechanisms that may explain taste reduction in COVID-19, compared to all the literature on anosmia. However, there are some possibilities:

1. Similar to the sustentacular cells in the olfactory epithelium, the supporting cells in taste buds may be vulnerable to CoV2 infection. The similar timing of olfactory defects is suggestive. Although no ACE-2 has been detected in taste buds, there is still too little evidence to overlook the possibility of supporting cell infection, especially given the tissue’s homology to the olfactory pathway that may insinuate a similar mechanism.

2. ACE-2 expression in the salivary gland suggests there may be dysfunction with regards to the flow of saliva. Saliva is the solvent for tastants entering the taste pore. Hyposalivation has been hypothesized to expose patients to greater risk of CoV2 infection since saliva usually has antimicrobial peptides (AMPs), key to innate immunity in the mouth. Further investigation into the role of saliva in loss of gustation is warranted. After all, RT-PCR tests in the clinic now detect early CoV2 levels from both intranasal swabs and saliva samples! Analogous to saliva, it would be interesting to look into the role of Bowman’s glands and nasal mucus on loss of smell in COVID-19.

3. Inflammation may play an indirect role on taste buds due to the infection of nearby, non-gustatory epithelial cells. The infected epithelial cells may secrete pro-inflammatory cytokines (messengers of the immune system), such as interferon, that can trigger apoptosis and lead to abnormal turnover of cells in taste buds. Infected cells may also secrete signals that may change the gene expression profiles of nearby cells, altering gustation. Inflammation, in summary, may result in a net loss of taste buds, a skewed population of cells in the taste buds or an altered epithelial structure disturbing sensory function. Future studies should distinguish between these potential changes.

4. Remember how there was a huge fuss about taking zinc supplements earlier in 2020? Zinc is the second most common trace mineral in your body after iron, with key roles in immunity and metabolism. Altered zinc homeostasis may be partly responsible for loss of gustation. Inflammation triggered by CoV2 infection may lead to zinc chelation and thus, acute hypozincemia (loss of zinc). Zinc is essential for gustatory cells and cranial nerves to maintain homeostasis. Some patients have actually shown improvement in taste perception with zinc supplementation. Zinc supplementation was popular for a hot second since it was shown to have an antiviral role in vitro: inhibiting coronavirus RNA polymerase activity. However, no hard evidence supports it has any role in treating COVID-19. Its antiviral effects may never reach effect if zinc does not enter infected cells in sufficient concentrations in the first place.

5. The CoV-2 Spike glycoprotein may occupy the sialic acid binding site on taste buds, accelerating the degradation of the gustatory particles. This may lead to loss of gustatory sensation. The affinity of Spike for sialic acid also suggested an alternative, low-cost, high affinity and fast detection method for testing in the clinic.

6. CoV2 may directly infect and damage the cranial nerves that transduce the gustatory information to the brain. This may somehow be linked to neurological disturbances in COVID-19.

All in all, most of the taste disturbances reported by COVID-19 patients are subjective and self-reported, so it remains unclear if any of these mechanisms, a combination of them or some variation of olfactory, gustatory and trigeminal input malfunction are responsible for the loss of taste. The impressive similarities across sensory systems, not limited to just olfaction and gustation, comes to show the value of drawing interdisciplinary parallels in order to further research and mechanistic understanding of diseases. Sensations, such as taste, which result from the combination of both gustation and olfaction, underscore how the 'whole' organism is functionally greater than its 'parts'. In the end, biology knows biology better than humans know biology, so highlighting these links is paramount to not miss the 'big picture'. For example, by observing how bacterial immune systems work, we uncovered the genetic editing tool of CRISPR! Harnessing these connections can yield a treatment to cure a broad range of conditions. The crazier, more absurd and risky the association, the greater the reward may be.

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