What Makes The Novel Coronavirus So Contagious?
Prion-like features may contribute to the transmissibility of COVID-19
The novel coronavirus that causes COVID-19, SARS-CoV-2, is significantly more contagious than the seasonal flu, and a preprint from the Human Microbiology Institute of New York may explain why. In this unpublished study, the authors examined the proteomic structure of the SARS-CoV-2 virus with computer modeling. They discovered that, unlike other closely related coronaviruses, SARS-CoV-2 contains prion-like domains in its receptor-binding spike proteins. These prion-like domains may contribute to a nearly 20-fold increase in affinity for the protein receptor found in human cells, ACE2. This unique structural element may contribute to the human-to-human communicability of COVID-19. So what are prions and why does it matter? Let’s start from the beginning.
How Coronaviruses Get Into Our Cells
At this point, we all know about the novel coronavirus causing the COVID-19 pandemic. The name “coronavirus” comes from the Latin word for crown or wreath, which refers to the visible structure of the viral particles in a cross-sectional microscopy image. But this two-dimensional description conceals the real shape of the viral particles — they’re more like spiky spheres than crowns or wreaths.
These spiky protrusions, aptly named spike proteins, play an important role in the replication cycle of all coronaviruses. As a quick and basic refresher, a virus doesn’t make copies of itself like most living things. Instead, it commandeers the cellular machinery of other lifeforms and uses the hijacked infrastructure to churn out more viral particles.
This parasitism allows viruses to be incredibly simple constructions with very small genomes. Because, unlike most of the genomes found in nature, viral genomes don’t need to encode for metabolic pathways, signaling molecules, or DNA replication machinery. The viral genome only needs to contain instructions for a few simple proteins. To put this into perspective, several million distinct proteins can be translated from the human genome, compared to just twenty-eight from the genome of the coronavirus that causes SARS.
The lifecycle of a coronavirus starts when one of these proteins, the spike protein, binds to receptors on a cell of its host. In humans, this receptor is angiotensin-converting enzyme 2, also known as ACE2. You may have heard of it from a widely used class of medications called ACE inhibitors that target these receptors to treat high blood pressure and other disorders. The coronaviruses underlying SARS and COVID-19 (as well as some influenza viruses) use ACE2 as a docking station to stick to the outside of cells. When a viral particle binds to these receptors it induces a natural process called endocytosis, in which the cell internalizes the receptor and the virus stuck to it. Once inside the cell, the virus will release its genetic material and the cell will start making copies of it. Those copies then leave the cell and repeat the cycle.
ACE2 seems to be both necessary and sufficient for COVID-19 infection to spread. In terms of sufficiency, the most common comorbidities for COVID-19 patients are diabetes, hypertension, and cardiac diseases, disorders that are often treated with ACE inhibitors due to increased expression of ACE2. In terms of necessity, it has been shown that the COVID-19 virus can be blocked from entering cells by preventing its binding to ACE2. The infectiousness of coronaviruses is driven by their ability to bind to ACE2.
Unfortunately, ACE2 may not represent a good therapeutic target, because inhibiting its activity causes all sorts of problems, like the severe lung damage that occurs in diseases like COVID-19. In fact, it seems like higher levels of ACE2 expression are correlated with lower levels of COVID-19 fatality and complications. This makes the story incredibly complex because higher levels of ACE2 make it easier for the virus to enter cells, but also make us more likely to survive and thrive as a result of the infection.
In a way, this makes the COVID-19 virus and other coronaviruses seem freakishly intelligent. It’s almost as if these disease-causing agents intentionally target a protein that plays a role in fighting them off. Even if we don’t ascribe intentionality or intelligence to coronaviruses, it is certain that they occupy a dangerous evolutionary niche from our perspective. By using ACE2 as an entry point into our cells they force us into a precarious balancing act. On the one hand, we can downregulate levels of ACE2 to lessen the risk of viral infection, but that leaves us susceptible to the damage caused by an infection. On the other hand, we can upregulate levels of ACE2, which makes infection more likely, but helps mitigate the resulting damage. It’s like a catch-22 between deadliness and contagiousness.
These viruses ensure their survival by maintaining an evolutionary arms race with their multi-cellular hosts. In this arms race, they force our bodies to choose between the risk of death or infection. But no matter which choice we make, viruses can respond by rapidly evolving in the other direction.
The rapid pace of viral evolution is precisely why we have such trouble with them as pandemic-causing agents. And COVID-19 has shut down global society in a way that previous outbreaks did not. So what has allowed this iteration of coronavirus to spread so much more effectively than its much deadlier cousins, MERS and SARS?
What Makes The Novel Coronavirus Unique
As PubMed says, “COVID-19 is an emerging, rapidly evolving situation.” The research being done is of such importance that the traditional peer-review process is being expedited or even bypassed. Therefore, all of what I’m about to say is speculative to some degree. Given that disclaimer, I’m fascinated by the results of an unpublished preprint about the function of the novel coronavirus’ spike proteins.
In this paper, researchers from the Human Microbiology Institute out of New York analyzed the amino acid sequence of the SARS-CoV-2 spike protein to see how it differed from other coronaviruses. They found that the S1 portion of the spike protein (the part that binds to ACE2) contains an intrinsically disordered region. This is exactly what it sounds like: the receptor-binding segment of the spike lacks a rigid structure.
So why does this matter? Because the function of a protein is largely determined by its shape, also known as its folding conformation. There are four distinct levels of protein structure:
- Primary structure: When proteins are first translated from RNA they come out as a simple, linear chain of amino acids.
- Secondary structure: Based on the charges of the constituent amino acids, the primary structure bends and twists into three-dimensional patterns.
- Tertiary structure: The 3D secondary structures interact with each other to create a more complex form, known as a folded polypeptide.
- Quaternary structure: Once tertiary structures form, folded polypeptides can interact with each other to create complexes — large, functional, multi-unit molecules that we colloquially call proteins.
Proteins need to be folded into the right shape to perform their proper functions. For example, hemoglobin proteins carry oxygen in our red blood cells — without hemoglobin, we would suffocate. The quaternary structure of the hemoglobin protein is made up of four polypeptides folded into very specific tertiary structures. One tiny change to the amino acid sequence (primary structure) of hemoglobin changes the way that its tertiary polypeptides interact with each other (quaternary structure), and this misfolding of the hemoglobin protein is the underlying cause of sickle cell anemia — a painful and incurable illness. Protein misfolding doesn’t always have such disastrous effects, but sickle cell disease exemplifies how the overall function of our body relies on the proper folding of the proteins within it.
When it comes to the novel coronavirus, the tertiary folding pattern of its spike proteins seems to affect its quaternary interactions, which changes its overall function. Unlike the related viruses behind SARS and MERS, which have fully structured spike proteins, the COVID-19 virus has a structured spike protein with a disordered region (see image below). This difference in the tertiary structure of the COVID-19 spike protein changes the way it interacts with the human receptor ACE2. Compared to the SARS and MERS viruses, the novel coronavirus binds to the ACE2 receptor 10–20x more tightly. And this can be explained by the intrinsic disorder of its spike proteins.
I think of it like a dumb game my family used to play: throwing noodles at a wall. A piece of uncooked spaghetti is rigid and will bounce right off the wall, but a well-cooked noodle is flexible and will stick firmly. To put this in terms of coronaviruses, the SARS and MERS viruses have more rigid spike proteins, but they are still sticky enough to sometimes bind ACE2 and enter our cells. However, the COVID-19 virus has a more flexible, “well-cooked” spike protein that binds to ACE2 more frequently and effectively. Unfortunately for us, the tighter these coronaviruses stick to our cells, the more easily they can infect us. In this way, the novel coronavirus can transmit COVID-19 from person to person with fewer viral particles. In the game of “spaghetti throw” the person who sticks the most noodles to the wall wins…
The flexibility of the SARS-CoV-19 spike protein may do more than just tighten its bind to ACE2. It has been suggested that the COVID-19 virus can infect cells by binding to another receptor, CD147. The novel coronavirus has improved upon the traditional routes of infection and simultaneously innovated new ways to get into our cells.
The intrinsically disordered region of the SARS-CoV-19 spike protein can help us understand how it has managed to achieve this enhancement in function. The structure of the spikes was originally described in an electron microscopy study, but the unpublished preprint from the Human Microbiology Institute takes this description one step further. This paper suggests that this intrinsically disordered region at the tertiary level has special functions at the quaternary level — these “prion-like” properties can explain the depth and breadth of its binding capabilities.
Why Prions (And COVID-19) Go Viral
As we saw with hemoglobin in the example of sickle cell anemia, a misfolded protein can be very damaging to physiological function. For this reason, cells have robust systems to ensure that newly translated proteins get folded correctly. And misfolded proteins that manage to evade those systems are swiftly degraded. But, sometimes, proteins will misfold in a very particular way that creates insoluble aggregates — clumps of dysfunctional proteins that cannot be broken down.
Protein aggregation can severely disturb cellular processes and is often deadly to cells. Cell death doesn’t always cause serious problems, because some cell types can be easily replaced. But when aggregation occurs in neurons (which can’t be replaced) it causes debilitating and life-threatening diseases. For example, Huntington’s, Parkinson’s, and Alzheimer’s diseases are all caused by protein misfolding and aggregation.
These neurodegenerative disorders are terrible, but they pale in comparison to an especially insidious group of illnesses known as prion diseases. Prions are a very specific kind of misfolded protein that can be caused by a genetic mutation, like the misfolded hemoglobin underlying sickle cell anemia. But what is particularly scary and unique about prions is that their misfolded conformations are contagious.
The most famous example of this is mad cow disease, which is caused by eating prion-infected meat. Once ingested, a misfolded prion can convert other proteins into the misshapen prion form (see the animation below). This process creates clumps of prions that unstoppably grow by recruiting normal proteins. Eventually, the misfolded prion form will spread throughout the body and disrupt all physiological functions. Prion diseases are invariably fatal.
Prion misfolding is an instance of how information can replicate. Although they are associated with the physical shape of a protein, prion diseases are more of a conceptual force than a physical thing. Prion diseases are caused by the spreading pattern of self-propagating protein folding. They can quite literally undergo evolution by natural selection. In this way, prions are very much like viral contagions in that they both represent infectious patterns of information. The relationship between viruses and protein misfolding goes much deeper than this article can explore. Suffice it to say that viral infections have been implicated in diseases like Alzheimer’s, in which misfolded protein aggregation plays a defining role.
Indeed, many viruses contain proteins with prion-like domains, but the novel coronavirus has started to use them to enhance its communicability. We’ve already seen that this provides a tighter adhesion between human ACE2 and the SARS-CoV-2 spike protein. The prion-like domain could also allow the virus to more easily jump between species with different ACE2 receptors by changing their conformation to be more amenable to binding. And while it is not confirmed that the COVID-19 virus can enter cells through additional receptors, its prion-like binding properties suggest that it could very easily find alternate routes to infect our cells. In other words, the COVID-19 spike protein may use the zombie-esque features of prions to convert human proteins into binding targets.
The respiratory symptoms and resulting death rates of SARS, and MERS are bad enough. And although COVID-19 is less deadly, the contagiousness it has gained from becoming more prion-like may be even worse. Hopefully, scientists will develop a vaccine and natural herd immunity will decrease the danger that this disease poses to society. But, until then, all we can do is learn and wait.
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