Welcome to today’s talk, presented by BioLegend. We’re going to briefly cover Coronaviruses, with a particular focus on COVID-19. We’ll then look into one of the stranger symptoms of the disease: olfactory dysfunction and the loss of smell.

Coronaviruses are a group of viruses that cause disease in mammals and birds. Infection symptoms may vary in different species. For example, coronaviruses cause respiratory tract infections in humans and chickens, and gastrointestinal symptoms such as diarrhea in cows and pigs.

Coronaviruses are amongst the largest RNA viruses with a genome of 26-43 kilobases. They contain an envelope or nucleocapsid that surrounds their positive-sense single-stranded RNA genome. The envelope also contains structural proteins that include membrane, envelope, and spike proteins.

Of the Coronaviruses, SARS-CoV-2 now has the world’s attention. To familiarize you with the terminology, SARS-CoV-2 stands for Severe acute respiratory syndrome coronavirus 2, and it causes COVID-19. COVID-19 stands for ‘coronavirus disease 2019’. The virus can spread from person to person when individuals come in contact with those who are infected or by coming into contact with infected objects or surfaces. The virus is released and spreads to the environment in the form of droplets or aerosols containing infectious viral particles through sneezing or coughing.

The main symptoms of COVID-19 include: fever, dry cough, shortness of breath, and fatigue. These symptoms can appear any time between 3 to 15 days after exposure to the virus.

In addition to the symptoms previously described, there is a distinct symptom developing among COVID-19 patients: the loss of smell and/or taste, also known as olfactory dysfunction. Altered olfactory dysfunction has been commonly observed in coronavirus infections like SARS. Some of the most relevant conditions consist of the following:
 

• Anosmia is also known as smell blindness. This is a condition that leads to the inability to detect one or more smells.
• Hyposmia is known as the reduced ability to detect odors.
• Dysosmia is a condition where the perception of smell is altered.
• And finally Ageusia is a term used for the inability to detect taste.

COVID-19 patients are most commonly affected by anosmia.

In order to understand how COVID-19 affects olfaction, it is important to understand the olfactory cells primarily affected. The nasal epithelium contains the sensory olfactory epithelium, which is composed of different cell types that have different functions. Mature olfactory sensory neurons, sustentacular cells, and basal stem cells are the main cell types that make up the olfactory epithelium.

Olfactory sensory neurons or OSNs are responsible for odor detection. When odor molecules bind to receptors on their surface, OSNs send a signal to the brain, which leads to sensing the smell. OSNs have a short lifespan because they live in a harsh environment and receive all kinds of insults passing through the nasal cavity. Therefore, they continually die & are replaced by new cells. However, OSNs don’t all die at the same time, so our sense of smell is not affected and we don’t notice their shedding.

Sustentacular cells are responsible for providing structural and physiological support for OSNs. For example, they can remove damaging agents and maintain local salt & water balance.

Basal stem cells are responsible for regenerating OSNs during normal epithelial turnover. They also act as reserve stem cells that are activated when tissues are damaged and can repopulate all cell types in the olfactory epithelium.

To characterize affected cells, we need the proper tools to detect them. Fortunately, olfactory cells express a number of cell markers that can be detected by antibodies and other reagents. For example, SOX2 is a marker for stem cells while Keratin 18 can be used to detect sustentacular cells. Beta 3 Tubulin and NCAM are marker often used to distinguish olfactory neurons from other cell types.

Which cell types in the olfactory epithelium are infected by SARS-CoV-2 and how? The virus uses two key host genes, ACE2 and TMPRSS2, to infect and gain entry into cells. A recent analysis of bulk and single cell RNA-Seq has identified that the stem cells and the olfactory support cells such as sustentacular cells in the olfactory epithelium express these two proteins. Using the same approaches, they also demonstrated that olfactory sensory neurons do not express either ACE2 or TMPRSS2. These studies show that SARS-CoV-2 causes anosmia by indirectly affecting OSNs through infection of non-neuronal cell types.

What are the potential mechanisms for COVID-19-related olfactory dysfunction? The spike glycoprotein expressed on SARS-CoV-2 envelope binds to the ACE2 protein expressed on supporting or stem cells. This interaction requires the cleavage of the spike protein by the host cell surface protease TMPRSS2. The virus is then able to gain entry into the cells and triggers a variety of host responses that can affect olfaction. Some of these responses include: inflammation-related damage and loss of olfactory epithelium cells including stem cells that replenish the pool of olfactory sensory neurons. The consequence of these responses could lead to a disruption in the global architecture of olfactory epithelium and loss of sensory neurons capable of detecting odor.

As a result of virus infection, odor signaling in the brain is disturbed and the sense of smell is affected. Since our perception of flavor is mostly tied to olfaction, many people also experience a loss of flavor. However, their sense of taste is still functional because the taste buds are intact and can distinguish between sweet, bitter, sour & salty tastes.

It is also possible that during SARS-CoV-2 infection, people experience something similar to what happens in common cold or flu: infected individuals experience a dullness in their senses of smell and taste due to a decrease in airflow through the nasal cavity, and increased inflammation or excess mucus in nostrils.

In summary, we have provided a general overview of coronaviruses and SARS-CoV-2, which causes COVID-19. We reviewed key olfactory system proteins and cell types involved in virus infection, and potential mechanisms by which SARS-CoV-2 affects olfaction and leads to anosmia. We hope you’ve found this talk informative and that it’s provided some insight into SARS-CoV-2, COVID-19, and the sense of smell. If you have any additional feedback, please contact us here.