Core Concepts
In this article, you will learn about the pathophysiology of coronaviruses, such as SARS-CoV-2, from a biochemical perspective. You will explore how these viruses cause infection in the body on a cellular level, and how these virus-cell interactions manifest as observable symptoms.
This is the first article in a special ChemTalk mini-series about the intersections between chemistry and public health, using COVID-19 as a case study. Across this series, you can expect to learn about the drug discovery and development processes, chemistry’s central role in diagnosing and preventing diseases, and careers that are on the front line of chemistry and public health.
What is a coronavirus?
All of us, over the past several years, have had a close-up view of something never-before-seen: COVID-19. We’ve witnessed the ways in which this pandemic turned our world inside-out. Now, let’s take a step back to examine the ins and outs of this public health pandemonium and the versatile virus that caused it.
SARS-CoV-2, a strain of coronavirus, is responsible for causing COVID-19. As we’ve seen, coronaviruses — named for the Latin word for “crown,” referring to its members’ structural garlands of proteins — can be a royal pain. Across recent history, other strains of this viral family have come and gone: for example, SARS-CoV-1 (whose early-2000s outbreak centered on East Asia) and MERS (Middle East respiratory syndrome, which has recurred several times in the past decade).
Both of these are examples of epidemics, an increase in disease transmission across a relatively short period of time. We call the most widespread of these, sometimes covering the entire globe, pandemics. Having touched practically every part of the world, COVID-19 belongs to this category.
How did COVID-19 spread in the first place? And what actually happens, on a cellular level, to infect someone and induce symptoms? The answers lie in its unique exterior protein — the same one that gives it its regal morphology.
How does SARS-CoV-2 cause COVID-19?
SARS-CoV-2 is a small virus with a big impact. In the early days of the COVID-19 pandemic, there were a lot of questions among biomedical researchers, public health experts, and the general public. We had encountered coronaviruses in the past, but COVID-19 was a novel disease. To figure out how to defeat it, first we had to determine how it spreads, and this wasn’t yet clear.
Let’s look at a single particle, or virion, of a coronavirus. Figuratively, of course — most coronavirus virions have a diameter of about 100 nanometers, making them far too tiny to see with the naked eye. Unfortunately, at times these miniscule dimensions can enable a virion to maneuver its way past our body’s defenses.
A Fast Track to the Respiratory Tract
Viruses require a host in order to replicate. If coronavirus virions enter a healthy person’s respiratory tract, the virions look for opportunities to embed themselves there. To do this, the virion must penetrate an uninfected cell in the respiratory tract.
The ability to do this lies in the crown-like sheath of proteins that we mentioned earlier. These spike proteins project outward from the virion in all directions. To make contact with an uninfected cell, a virion’s spike protein must bind with a complementary receptor on that cell’s membrane. As a virion moves through the respiratory tract, being encased with spike proteins on all sides maximizes the virion’s chances of binding to a suitable receptor along the way.
Sometimes, cells and structures in the upper respiratory tract (the nose, mouth, and throat) can prevent the virions from going any farther. For instance, cilia in the upper respiratory tract physically propel virions away from the lungs before they can infect any respiratory cells. The body can then expel the virions in the form of an exhale, a cough, or a sneeze. But if the virions manage to evade this frontline defense, they may reach respiratory cells in the trachea and lungs, at which point infection is much more likely.
The Architecture of a Coronavirus Virion
At the core of its existence, a virus has a dual purpose: to infect a host, and to spread that infection to additional hosts. Equipped with several proteins designed to make infection as efficient as possible, the coronavirus virion carries out this mission. Let’s look at each of these proteins in greater depth, starting from the inside and moving outward.
Lying at the center of the virion is a structural nucleocapsid of N proteins (“N” for “nucleocapsid”). The capsid contains and shelters the most vital part of the virion: its RNA. Without RNA, the coronavirus would not be able to replicate itself and spread infection to new hosts. N proteins neatly package the virion’s genetic material for safekeeping until the virion has successfully infected a host cell, where it can replicate.
You’ve Got Mail! How the Viral Envelope Delivers the Virion to Host Cells
All coronaviruses are enveloped viruses, meaning that they have an external phospholipid bilayer protecting the capsid. This envelope has two critical functions. First, it shields the virion’s genetic material from damage while the virion traverses the respiratory tract. The virus can only replicate inside of a cell, so it must protect its genetic material until it can enter one. Second, the viral envelope facilitates entry into a respiratory cell once the virion reaches one. Since the cell’s outer membrane is also made of a phospholipid bilayer, it readily fuses with the coronavirus’s envelope, inviting the virion into the cell. At this point, the cell is now a host cell.
Embedded in the virion’s envelope are three proteins. The M protein (where “M” refers to “membrane”) is thought to control the assembly of new virions. This assembly happens after a virion replicates itself — more details on that soon. Throughout the envelope we also find the E (“envelope”) protein, which helps form ion-channel–like structures in the virion’s envelope and in an infected host cell. After new virions get assembled, these channels regulate the release of those newly-assembled virions from the host cell. The E and M proteins are both transmembrane proteins, spanning the entire thickness of the virion’s envelope. By contrast, protruding from the envelope on the virion’s exterior are S proteins (“spike” proteins).
Remember that a coronavirus virion uses its spike protein to guide it into a host cell. More broadly, this ability of a virion to recognize a particular type of cell is called viral tropism. It’s the means by which the virion decides whether to infect a specific host cell over a different kind of host cell. Notably, SARS-CoV-2 tends to infect host cells with a certain attribute: a unique receptor known as ACE2. Next, we’ll see how a virion’s spike protein interacts with the ACE2 receptor to fulfill the virion’s mission of infecting cells.
How does COVID-19 interact with the body’s cells?
Consider the respiratory tract itself, lined with epithelial cells which serve as a barrier between the body’s respiratory tract and the external environment. Many of these epithelial cells in the lungs, nose, and mouth contain a receptor called angiotensin-converting enzyme 2 (ACE2). ACE2 is another transmembrane protein, bridging the distance between the interior and exterior of the epithelial cell. It is also capable of attaching to the receptor-binding domain of a SARS-CoV-2 virion’s spike protein. When this binding happens, it triggers receptor-mediated endocytosis, packaging the virion inside of an endosome and delivering the endosome into the host cell. Let’s look at this process on a cellular level.
Before and After Binding
Each spike protein on the virion consists of three S1 subunits and three S2 subunits. S1 subunits form the broad end of the spike, while S2 subunits comprise the more narrow stem. The S1 subunits collectively drive the binding of the virion to the host cell’s ACE2 receptor. Then, the S2 subunits enable the virus to fuse with the host cell’s membrane. All coronaviruses have spike proteins, and their S2 subunits are fairly conserved. By contrast, we see more variation in the S1 subunit across different types of coronaviruses.
Prior to binding, the spike protein is in a “closed” conformation. In the closed conformation, steric hindrance prevents the S1 subunits from effectively binding to an ACE2 receptor. These subunits’ receptor-binding domains are not exposed, so binding can’t happen. The magic happens when host proteases cleave the spike protein at specific sites, including the site between the S1 and S2 subunits. Several host proteases are involved, but a prominent one is transmembrane protease, serine 2, made from the TMPRSS2 gene. This protease cleaves peptide bonds, so its activity exposes the spike protein’s S2 subunits from the larger ACE2-S1 complex. This exposed state is the “open” conformation.
Cleavage must happen in order for binding to become possible. Once this open conformation stabilizes, the S2 subunits guide the fusion of the viral envelope to the host cell’s membrane. Successful binding allows the virion to fuse with and penetrate the host cell’s membrane. Finally inside the host cell, it can begin to replicate.
One could say that the ACE2 receptor is a necessary evil. In humans, it regulates blood pressure and electrolytic balance, and therefore is important to cardiovascular health. Unfortunately, the SARS-CoV-2 virus has evolved to hijack ACE2’s normal cellular mechanisms so as to gain entry into human epithelial cells.
Once inside of a host cell, the endosome breaks open, freeing the virion within the cell’s cytoplasm. At this point, the virion uncoats, which involves the degradation or dissociation of its envelope to expose its genetic material. Now, the virion can undergo replication as part of its viral life cycle, utilizing the host cell’s normal replication machinery. Unlike some other viruses which have DNA, coronaviruses are RNA viruses and use RNA as their genetic material. Their genomes are among the largest of all RNA viruses, with most falling between 26 to 32 kilobases (kb).
SARS-CoV-2’s genome is toward the middle of this range, and the host cell’s ribosomes translate it just as they would translate typical messenger RNA. Meanwhile, the cell’s endoplasmic-reticulum–Golgi intermediate compartment (ERGIC) assembles progeny viruses, identical copies of the virus. In the ERGIC, new M proteins are synthesized in order to carry out assembly.
After translation and assembly, the newly-created progeny viruses undergo exocytosis, encapsulated in vesicles as they exit the cell. This step is known as budding. Through budding, the progeny viruses end up with envelopes of their own. These envelopes are made of the same lipid bilayer that the host cell’s membrane is made of. Budding doesn’t directly kill the host cell, but oftentimes infection weakens the cell to the extent that it dies anyway.
Once in the extracellular environment, the progeny viruses seek out new, uninfected host cells. By latching their spike proteins onto uninfected cells’ ACE2 receptors, the progeny viruses can penetrate these cells, kickstarting the viral life cycle again.
Chasing a Moving Target
The spike protein is significant for two reasons. First, as we’ve learned, a coronavirus virion uses the spike protein to invade a healthy host cell. Second, some of our cutting-edge defenses against these viruses target these specific spike proteins.
Inventing an mRNA vaccine against COVID-19 is one of the measures that ultimately helped manage the spread of the disease during the later half of the pandemic. We will explore the vaccine development process in a future article within this series, but for now you should understand that these vaccines make the body produce proteins that resemble the SARS-CoV-2 virion’s spike protein. This teaches the body’s immune cells what the actual virion’s spike protein looks like. In the event that you get infected, your body’s immune cells will recognize the spike protein on SARS-CoV-2 virions, and will attack them.
A Shapeshifting Virus
The problem is that a coronavirus, such as SARS-CoV-2, is capable of mutating. Mutations happen all the time in nature, and at the simplest level are one nucleotide being transformed into another in a DNA sequence. Mutations occur randomly and sometimes do not cause any change in the virus or cell. Sometime, however, they can alter viral or cellular functions, either positively or negatively. When a virus mutates into new variants, the new variants may have unique spike proteins compared to the original strain. (We’ll talk more about different variants shortly.) The virus can mutate to the point that, even after vaccination, the body doesn’t recognize the new variant’s spike protein because it looks so different from the spike protein introduced by the mRNA vaccine. If the virus has mutated sufficiently, it may evade the body’s immune system altogether, and the vaccine becomes less effective.
Although it’s a remarkable innovation, a vaccine tailored to a particular variant of coronavirus is a double-edged sword. It’s a valuable tool in helping us reduce the spread of devastating and fast-moving variants. For example, after the destructive Delta variant of SARS-CoV-2 emerged in late 2020, researchers started working on a vaccine that could address the Delta variant in addition to the original strain. (Here, let’s note that it’s possible to make a single, polyvalent vaccine which fights multiple variants of a virus.) However, if a vaccine is highly specific in targeting one variant, it may not be able to target any others. The vaccine is almost self-limiting in this way, as its most purposeful feature can also be a potential disadvantage.
Virus Mutations: A Delicate Balance
As we saw previously, viruses can’t survive without a host cell. Upon finding a suitable host cell, a coronavirus virion enters the cell, commandeers its replication machinery, and kills it, releasing more virions as a byproduct.
This strategy is also a double-edged sword. The virions’ goal is to infect as many host cells as possible to maximize their own spread. But, if the virions kill too many host cells through this process, there won’t be enough host cells remaining for them to infect next. And if the disease is deadly, like COVID-19 can be, the host itself (the COVID-19 patient’s body) may die from the infection, preventing the virions from infecting any new cells in that host. In other words, the virus must make an effort to infect a host, but it can’t be too good at infecting a host, or else it won’t be able to continue spreading disease.
The replication of virions in host cells causes variants over time to become less deadly and more infectious. It also is why not all mutations lead to significant changes to the virus. If a mutation happens to make a virus less infectious or deactivate an essential process entirely, then the virus will not be able to replicate, and those mutations will not spread into new viruses. Remember, mutations happen randomly, but only mutations that eventually aid in replication will be passed down to new generations of the virus.
One Big Happy Family: Strains, Variants, and More
Within the realm of coronaviruses, we see a lot of diversity. The distinctions between individual coronavirus species are largely due to mutations that they undergo. Mutations can happen on several different scales.
Let’s say a particular virus has mutated a lot over time. Eventually, after enough mutations, it may be considered an entirely new virus species. However, not all changes are large enough to establish a novel species. By tweaking just a small portion of its genome, a virus can evolve into a new subtype of that virus. If the resulting subtype has similar behavior and biochemical properties as the original virus, we call this subtype a variant of that virus. If the subtype has significantly different behavior or traits, it is a different strain of the original virus.
We can break this down even further. Over the past few years, for instance, you may have heard descriptions of COVID-19 subvariants in the news. Subvariants are like a middle ground between variants and strains. In other words, a subvariant has distinct differences from the original virus, but these differences are not quite substantial enough to designate this new subtype as a variant.
A virus’s characteristics change due to mutations in its genome. Small modifications in the virus’s genetic material can lead to new behaviors or features. It’s possible to genetically engineer a virus, where researchers manipulate the virus’s genetic material to confer specific properties upon it. One growing application of this is gene therapy to help resolve medical issues caused by genetics. For example, scientists can introduce functional or healthy genes into the DNA of adeno-associated viruses (AAVs), and then infect patients with the AAV. When the AAV reaches the patient’s own cells, whose DNA is causing a medical issue, the AAV delivers the functional or healthy DNA into these cells. The goal of this process is to manipulate (mutate) a virus’s genome to help improve a patient’s health. These patients depend upon the virus mutating in controlled ways that are ultimately beneficial to them.
That said, viruses can mutate naturally too. And natural mutations aren’t controlled or overseen by genetic experts who know how to harness the mutations’ power for a good cause. Mutations can happen naturally when the virus replicates — an important and necessary step in its life cycle. Every time a virion’s genetic code is replicated to create progeny viruses, there’s a chance that this genetic code may change. Sometimes these changes happen by accident. Sometimes they have no effect at all, and other times, they prevent the virus from successfully replicating itself. But if the virus survives despite these changes, the changes might bestow new properties or behavior upon it.
This is what we observed throughout the COVID-19 pandemic. Many of the tactics we used against SARS-CoV-2 served as a direct blow: mRNA vaccination efforts, virucidal cleaning agents, and the list goes on. Plus, many people gained immunity to the disease as a consequence of getting infected. All of these factors meant that, in order to continue posing a threat to us, SARS-CoV-2 had to mutate to make itself more robust in the face of our efforts. Let’s briefly take a look at what these mutations looked like in the context of COVID-19.
COVID-19 Variants
As new SARS-CoV-2 variants arose during the pandemic, key epidemiologic trends arose, too. Looking back, we can identify clear “waves” of the COVID-19 pandemic. After the original strain took its course, each subsequent wave escalated because a new variant came into the picture. Waves declined once that specific variant had run its course, when a more impactful variant presented itself, and as our collective immunity began to surpass infection rates.
There have been many SARS-CoV-2 variants and subvariants. You may know some of them by their enigmatic names: sometimes a cryptic string of numbers and letters or, if that wasn’t intriguing enough, Greek letters. Rather than decode these names, let’s review some of the more memorable variants, and particularly, what made them so potent.
In October 2020, almost a year after the earliest COVID-19 cases, public health officials observed a new variant in India. It appeared to spread faster than ever (an especially concerning circumstance in heavily-populated India), and was reinfecting individuals who had survived the original strain. To make matters worse, effective COVID-19 vaccines were still in development at that time, and not yet available to the public.
What made this variant, Delta, so elusive were mutations in its S protein, which made the virus more adept at infecting people. In Delta virions, the spike protein that binds to human host cells has a stronger affinity for the ACE2 receptor than the original strain of SARS-CoV-2 has. This means that Delta wielded a higher transmissibility and, in some cases, successfully dodged the body’s natural immunity response, including antibodies resulting from a previous COVID-19 infection.
Where did these new characteristics come from? Over 1,000 amino acids constitute one S protein on a SARS-CoV-2 virion. (Other coronaviruses’ spike protein lengths may differ from this.) That represents over 1,000 opportunities to mutate, and sometimes a single mutation has a disastrous effect on public health. Most of the identifiable mutations that created the Delta variant are substitution mutations, where one amino acid replaces another. One example is the P681R mutation, which happened when an arginine residue replaced a proline residue at position 681. This simple change is thought to facilitate the cleavage of the S protein, which, as we discussed, has a central role in driving host cell infection.
Delta finally dwindled and petered out in mid-2022. If it feels like Delta disappeared before that, however, you might feel that way because newer variants of concern had already popped up by then. One prominent variant in this category is the Omicron variant, which surfaced in Botswana in November 2021. When it was the dominant variant, Omicron had the most mutations (approximately 50) of any SARS-CoV-2 variant until that point. In addition to various substitution mutations, Omicron’s spike protein also featured insertion and deletion mutations, making its genome even more unique than previous variants. Some of these mutations happened in the S protein’s receptor-binding domain, the hotspot where the virion attaches to ACE2. This speaks volumes about Omicron’s markedly increased transmissibility, especially noticeable in its BA.2 subvariant.
Omicron was even more contagious than Delta had been, but the game had changed by this point. First of all, COVID-19 vaccines had been released to the public and were gradually becoming more readily available worldwide. Secondly, for most people who caught it, the Omicron strain was noticeably less severe than previous variants and the original strain had been.
Omicron patients had lower frequencies of classic COVID-19 symptoms, such as a loss of smell and taste. One theory is that whichever mutation made Omicron more transmissible than ever also made Omicron less capable of deeply penetrating respiratory tissues. Generally speaking, if SARS-CoV-2 penetrates respiratory tissues more deeply, symptom severity tends to increase. This is because the respiratory tissues are the heart of the operation: they’re where the virus infects the host, replicates itself, and creates progeny viruses.
Let’s briefly revisit the waves of the COVID-19 pandemic. A wave is distinguished by the dominant strain or variant at that time. In retrospect, epidemiologists can use this high-level overview, called genomic surveillance, to trace the history of when different variants arose and how quickly they spread throughout a population — or the world.
Using the graph above, we can visualize some significant trends. First and foremost, waves are clearly visible across the four-year–period displayed. Each wave indicates when that variant was the predominant one circulating in the U.S. You’ll also note that “other” variants are predominant early in the pandemic and (as of this article’s publication) since mid-2023. The original strain, which is not a variant, represents the “Other” category until late 2020. In other words, practically all COVID-19 infections in the U.S. belonged to the original strain of SARS-CoV-2 until the first known variants arose in late 2020. Contrarily, the “Other” category since mid-2023 encompasses a wide range of variants and subvariants besides those specified in the graph. This includes the many subvariants in non-BA lineages of Omicron.
Mutations help explain why coronaviruses are so diverse. But keep in mind that mutations can happen to other viruses too (or to any organism that has genetic material, really). Ultimately, like any other species, viruses evolve in order to adapt to and thrive in their dynamic environments. Don’t forget that, as the pandemic progressed and we adapted to living with COVID-19, SARS-CoV-2 has had to adapt to living with us as well.
Mutations and Vaccines
At the time of this article’s publication, SARS-CoV-2 continues to mutate, even though many countries have adapted to manage the spread of COVID-19. Any feature of the virion can mutate, but public health officials are especially concerned about mutations in the virion’s spike protein. Since the COVID-19 vaccine pertains to the spike protein, changes in the spike protein could render existing vaccines ineffective. In SARS-CoV-2’s case, the spike protein’s ongoing mutations complicated the vaccine development process over several years.
The spike protein’s ability to mutate may provide some retrospective insight as to how new coronaviruses surface. One theory as to how SARS-CoV-2 evolved suggests that the virus may have originated in a host in nature, an animal reservoir such as a bat, and its spike protein mutated so that the virus was then able to infect human cells. However, this is still a point of debate among biomedical researchers and public health experts. We may never conclusively determine how the first COVID-19 case materialized, and whether or not it descended from an animal host.
The COVID-19 Conundrum: A Public Health Perspective
In the wake of a disease outbreak, an efficient public health response is essential. Well-orchestrated strategies can be instrumental in containing and putting an end to the spread, which goes a long way in minimizing negative outcomes on the economy and human health.
As COVID-19 established itself in our lives, epidemiologists used early cases to study precisely how SARS-CoV-2 spread. They found that this virus is transmitted primarily through the air. This observation led to the introduction of public health policies such as social distancing and the use of face masks: limiting contact between infected patients and health individuals whenever possible, and, when this wasn’t possible, enforcing physical barriers between their respiratory tracts.
The act of exhaling releases respiratory droplets from the lungs into the air. In a healthy individual, these droplets contain matter from the inside of the lungs: saliva, mucus, and the electrolytes in those fluids. When a coronavirus patient exhales, their respiratory droplets also contain virions, sometimes hundreds of them. As a byproduct of respiration, these droplets can potentially spread anytime someone breathes: when they talk, cough, sneeze, and even when they exercise or sing.
The Difference Masking Makes
Close contact with an infected person, especially for an extended period of time or if neither of you are wearing masks, increases your risk of contracting the virus. This is why, when COVID-19 was found to be spread through droplets, many public health policies closed or restricted places where people gather in close proximity. Your favorite band’s concerts got postponed over and over again, your flight got canceled after months of careful vacation-planning, and you had to start working out at home instead of at the gym.
Given how transmissible later variants of the virus became, using effective face masks was crucial to reducing new infections. Face masks are a form of personal protective equipment, or PPE. (You might already be familiar with some other forms of PPE that are common in chemistry laboratories, like gloves and protective eyewear.) However, using a mask doesn’t make you invincible.
Depending on their size, some respiratory droplets transporting virions can slip through the pores of a standard surgical face mask. As such, the COVID-19 pandemic saw discussions as to what types of masks work best as a barrier against SARS-CoV-2. Surgical masks were an everyday sight throughout the entire pandemic, but new scientific research gradually indicated that other mask styles may better protect against COVID-19 infection. For example, N95 respirators are a type of mask that utilize an extra layer of filtration compared to surgical masks. When fighting an airborne pathogen, every layer of protection counts.
How do COVID-19 symptoms arise?
From its origin in the respiratory system, a coronavirus infection can spread near and far to other parts of the body. Each new host cell that gets infected along the way has the potential to spread the infection to many other cells by making and releasing new virions. As the disease reaches new body regions, it impacts the cells there, giving rise to a variety of perceptible symptoms.
Respiratory Symptoms of COVID-19
Recall that, after being assembled, progeny viruses depart the dying host cell in search of a new healthy host cell to infect. The infection typically begins when a COVID-19 patient transmits their contaminated droplets to a healthy individual. Upon the healthy individual inhaling these droplets, the virus now has access to that person’s respiratory cells. As a result, some of the most prominent COVID-19 symptoms pertain to the respiratory system: a persistent cough, a sore throat, and difficulty breathing.
Two factors are largely to blame for symptoms like these. First, the virus directly damages host cells in and around the respiratory tract. Depending on where in the respiratory system these cells are, cell damage can interfere with key functions like proper gas exchange. This contributes to symptoms like shortness of breath. Additionally, inflammation from the body’s immune response can lead to respiratory symptoms. After an infection begins, immune cells act fast to pursue and attack SARS-CoV-2–infected respiratory cells. This hot pursuit is what causes inflammation, alongside other symptoms like swelling. (Of course, the airways are one place where you don’t want to experience swelling.) Some respiratory complications of COVID-19, like pneumonia, feature swelling of the lung tissue and cause lasting cell damage even if the patient survives.
In some cases, a patient only experiences respiratory symptoms. But for other patients, a wide range of non-respiratory symptoms can appear too. One of the most perplexing symptoms, first observed early on in the COVID-19 pandemic, is a loss of smell or taste (or both). Also commonly reported were muscle aches, nausea, and fever.
We’ve already discussed how coronaviruses spread between people, but what about within a person? If you experienced a coronavirus infection firsthand, these sensations probably sound familiar to you. They’re evidence of the virus spreading throughout a patient’s body — putting down roots in the respiratory system, then gradually impacting cells elsewhere in the body as the disease progresses. Let’s consider some of these symptoms one by one.
Non-Respiratory Symptoms of COVID-19
Although we interpret scents and tastes in the nose and mouth, these senses aren’t part of the respiratory system. Instead, our abilities to smell and taste are functions of the nervous system. The brain receives information about odors from the nose’s olfactory neurons, and information about tastes from the tongue’s gustatory cells. It’s easy to think that, when a COVID-19 infection limits your senses, the virus must have damaged these sensory cells. However, this isn’t necessarily the case.
The Emergent Effect of Epithelium
Olfactory neurons in the nasal cavity and gustatory cells in the mouth are each embedded in layers of epithelium. Sound familiar yet? This layer’s cells, like the ACE2-rich epithelial cells of the respiratory tract, are vulnerable to coronavirus infection and subsequent damage. In response to the presence of the virus, the body’s immune system may ramp up inflammation. So, even though we observe a loss of smell or taste, SARS-CoV-2 hasn’t necessarily damaged our olfactory neurons or gustatory cells. Rather, the virus (or the inflammation intended to destroy it) has damaged the delicate epithelial tissue around those cells.
Similarly, epithelial cells and their ACE2 receptors exist in muscles, the spinal cord, and the depths of the gut. These cells are susceptible to COVID-19 infection too, manifesting as aches, gastrointestinal symptoms such as nausea, and more. Meanwhile, fevers aren’t unique to coronavirus cases, but they’re a general sign that the body is fighting an illness. As infected host cells manufacture and release progeny viruses, body temperature increases to become as inhospitable an environment as possible. It’s the body’s noble effort to try to deprive the virus of the conditions it needs to survive.
With other body systems affected now, the infection is capable of wreaking havoc on a greater scale. In severe cases, COVID-19 spreading within the body can cause complications like multiple organ dysfunction syndrome, sepsis, and permanent injury. Luckily, if the patient survives, inflammation and discomfort may eventually ease, alleviating their symptoms and returning their senses to normal. But what about the in-between cases, when patients clear the infection but their health isn’t fully restored?
Long COVID
Symptoms may come and go over the course of a COVID-19 infection. But for some unfortunate patients, their symptoms still aren’t fully resolved months or years later. This observation is puzzling, intriguing, and for these patients, downright disruptive to their quality of life. We call this long COVID, a condition when COVID-19 symptoms persist after the initial infection subsides.
Long COVID may be experienced in a wide range of body regions, not just in the respiratory system. Some patients continue to have a distorted — or completely absent — sense of smell or taste for an extended time. Others feel exhausting fatigue or brain fog, interfering with their ability to function on a day-to-day basis. In cases like these, the aftermath of the disease can be even more dreadful than the infection itself.
What causes long COVID?
Any COVID-19 survivor, not just those in vulnerable populations or who experienced severe cases, can end up with long COVID. Long COVID is uncharted territory, so it’s hard to predict who might experience it. It’s even harder to determine why it happens.
Leading theories suggest that symptoms persist due to an ongoing autoimmune response, where inflammation continues as the immune system attacks bodily tissues. Perhaps the chronic symptoms happen because the body never fully cleared the virus in the first place, or due to the aftereffects of tissue damage sustained during the original infection. Some tissues, like pathways in the nervous system, can take a long time to fully recover from damage. This could explain symptoms that reflect neurological dysfunction or involve pain. When the virus infects epithelial cells in the digestive tract, this could cause long-term imbalance in the gut’s microbiome, launching a whole host of gastrointestinal symptoms.
It’s clear that COVID-19 infection can have a lasting effect on patients during the infection, afterward, or both. This is a disease that can impact every patient differently. So differently, in fact, that some patients don’t even know they have it.
No COVID?
Symptoms may come and go … or they may not come at all. As we’ve adapted to life with SARS-CoV-2, so too has the virus adapted to living with us. Instead of classic COVID-19 symptoms like sensory changes and trouble breathing, present-day patients’ symptoms are more likely mild and flu-like. How is this possible?
Throughout the pandemic, we’ve seen how SARS-CoV-2, even the same strain, can affect populations differently. Patients who are elderly, immunocompromised, or who have underlying medical conditions tend to experience worse symptoms than younger, healthier individuals. Not only that, but these less-affected individuals sometimes display no symptoms at all, which raises a lot of questions for public health and biomedical researchers.
The HLA Gene
The answer may lie in the human leukocyte antigen (HLA) family of genes. With these genes’ guidance, the immune system is able to discriminate between the body’s cells and foreign invaders. The immune system’s antigen-presenting cells consume SARS-CoV-2 virions via phagocytosis. After phagocytosis, peptide remnants of the virion are displayed on HLA proteins residing on the outside of the host cell. These HLA proteins act like a flag, informing T cells of the infection and drawing the T cells close enough to kill the host cell.
Although it seems like the immune system is sabotaging the body’s own cells, this technique actually curbs the virus’s spread. Working as a team, T cells and antigen-presenting cells kill the infected cell before it can produce progeny viruses. Regulating the immune system in this way, especially during an active infection, is crucial to limiting the spread of the infection and protecting other potential host cells.
Everyone has HLA genes, but these genes come in many forms. The HLA-B gene, in particular, and its alleles are thought to play a role in asymptomatic coronavirus cases. Its protection appears to be additive, too, with studies indicating that homozygous carriers of the HLA-B*15:01 allele are less likely to show symptoms than patients who have no or only one copy of this allele. This allele is correlated with memory T cells, which recognize SARS-CoV-2 peptides and trigger the immune system to swiftly destroy the host cell. To an extent, an individual’s resistance to COVID-19 may be due to their biology.
Other Theories about Coronavirus Resistance
Asymptomatic transmission became an even bigger concern as the pandemic advanced, because later variants evolved to cause less intense symptoms. Some COVID-19 survivors who later get reinfected with a new variant notice a difference in the severity of their symptoms between the two infections. Oftentimes, the original infection was more severe than the reinfection. This may be because COVID-19 survivors have some immunity to the disease already, since their immune systems encountered it before. Another factor that influences this phenomenon is the notion that newer coronavirus variants are evolving to cause milder symptoms.
Why do newer variants exhibit this decreasing intensity? It all goes back to that delicate balance that SARS-CoV-2 has to strike. As the pandemic continued, more people gained immunity through vaccination or surviving an infection (or both). Generally speaking, the most vulnerable people exposed had already succumbed to the infection. This essentially means that the virus was running out of vulnerable hosts to infect. Since coronaviruses only survive with a host, it was in the virus’s best interest to cause milder symptoms with a lower mortality rate. (However, this evolution didn’t necessarily change the frequency of long COVID among survivors.)
The same principle is at play when it comes to vaccination. Someone who receives a COVID-19 vaccine gains a level of immunity against the disease. Even if a vaccinated person later gets sick, their symptoms tend to be milder than those of unvaccinated patients. This effect is common regardless of whether or not the vaccinated person previously survived the infection before getting the vaccine. And it’s another meaningful purpose behind vaccination: not just to stop the infection in its tracks when possible, but also to reduce the infection’s harm when that’s not possible.
Conclusion
Understanding on a biochemical level how coronaviruses function and spread was an important first step in the COVID-19 pandemic response. Public health experts built upon their existing knowledge of other coronaviruses, but managing outbreaks proved to be a challenging race against time, especially as SARS-CoV-2 evolved into new variants. Coronaviruses are characterized by their crown of spike proteins, which bind to a host cell’s ACE2 receptors, permitting entry. Once inside, the virus replicates itself by taking over the host cell’s natural translation hardware. These progeny viruses then infect new cells throughout the body, escalating the infection unless the immune system successfully intervenes. Every COVID-19 case presents uniquely in terms of physical symptoms and their severity, forging our fascination with the disease even further, and adding to the riddle of how to resolve it.