5 Quotes to Convince People You Understand COVID-19 Biology

Sun Tzu once said, “Know thy enemy”...Let’s get to know our enemy virus in the midst of this pandemic! Or, at least, let us flex that we understand the biology using these 5 easy quotes:

#1. “SARS-CoV2 is the virus. COVID-19 is the disease caused by the virus.”

Published media use SARS-CoV2 and COVID-19 interchangeably, however, the two terms hold very different meanings. 

SARS-CoV2 is an acronym for Severe Acute Respiratory Syndrome (SARS) (Co)rona(V)irus 2. It is the second virus in the Coronavirus family to cause SARS, after SARS-CoV1 in the 2002-2003 epidemic. The virus was originally called 2019-n CoV (‘n’ meaning novel and 2019 being the year it was discovered to be virulent in humans). However, this name was quickly overturned once the genotype of the virus was better understood. In fact, the CoV2 virus is 96% similar to CoV1, which has sparked several conspiracy theories of it being engineered for biowarfare. 

Moreover, the ‘novelty’ of this virus in its original name, 2019-n CoV, was deemed misleading since this virus is not really novel at all. Hundreds of coronaviruses have been identified in bats, with incredible diversity, making it highly unlikely this is the last CoV spillover we will see in our lifetime. In addition to the widespread coronavirus strains that cause the common cold such as HCoV-OC43, there have already been 3 CoV epidemics in the past 20 years alone. As you can see in the diagram below, coronaviruses originally found in bats naturally evolved to acquire a gain of function mutation that allows them to infect new hosts. Mutations and proximity to carrier species perpetrated the zoonotic spread of infection.

On the other hand, COVID-19 is the disease in humans resulting from the physiologic reaction to the virus infection. COVID-19 is shorthand for (Co)rona(vi)rus (D)isease 20(19). In other words, SARS-CoV2 finds a home in our body, using our cell machinery to replicate so it can then burst out of, damage and infect more cells. Our body reacts to this foreign and harmful virus by over-activating our immune response which manifests as symptoms in patients. These symptoms are the evolutionarily programmed mechanisms designed to create an unfavorable environment for the virus to call home, while simultaneously encouraging the patient to rest.

Therefore, just as HIV (Human Immunodeficiency Virus) leads to the disease AIDS (Acquired Immunodeficiency Syndrome), SARS-CoV2 leads to the disease, COVID-19.

#2. “The core of the virus grants infectivity, while the exterior of the virus grants specificity”

The core of SARS-CoV2 contains the viral genetic RNA code, which is the blueprint that dictates everything for the virus: from the structure of the proteins that coat its surface to the very enzymes that replicate it and outsmart host immune attack and degradation. For instance, upon entry into the cell through endocytosis, the virus contains proteases (enzymes that cut proteins) that manage to degrade the vesicle it is encapsulated in so that its RNA can escape into the cytoplasm to get transcribed by the host cell ribosome. Otherwise, the endocytosed vesicle containing the virus would have been destined for degradation by the lysosome, which contains acidic reactive oxygen species and proteolytic enzymes called cathepsins. Therefore, the only thing needed for the virus to replicate itself and create infectious progeny virions is its genome, as it is the only thing that needs to escape into the cytoplasm from the endosome. Notably, without access to host cell machinery, the virus would not be able to replicate, hence why viruses are not considered living things: they depend on another host for survival and reproduction. 

On the other hand, the exterior of the virus grants specificity since the proteins on its surface bind specifically to a particular receptor on host human cells. These proteins include: Envelope (E), Spike (S), Nucleocapsid (N) and Membrane (M) proteins. The numerous proteins on the surface of the coronavirus gives it a crown-like appearance, hence the latin root “corona”, meaning crown. The type of cells the virus can infect depends on what it can latch on to. For instance, ACE-2 receptors are present in the lung, hence the pathology, cell death and resulting shortness of breath observed in COVID-19 patients. Meanwhile, a cell type on another tissue that does not express ACE-2 would not have a portal for the SARS-CoV2 to bind and enter through. Therefore, these cells would not be infected.

#3. “SARS- CoV2 is part of the Coronavirus family: an enveloped, positive sense single-stranded RNA virus with a very large 30kb genome that can hijack cell machinery to reproduce itself.” 

Although not living things, viruses are referred to with the same Linnaean taxonomy (system of classification), hence the term Coronavirus “family”.

Enveloped viruses are often easier to degrade since detergents and surfactants (such as Lysol!) can permeabilize or “poke holes in” the cell membranes. Unfortunately, injecting Lysol or detergents, per Trump’s recommendation, is not safe since this would not only kill off the virus, but also our own cells (wild: our cells also have cell membranes). The last thing we want is to burst our own cells, which is what the virus does anyway when a lytic rupture releases replicated viral particles that were hidden inside the cytoplasm.

A hallmark of Coronaviruses, a positive sense, single stranded RNA genome is convenient since it can be directly recognized and transcribed by host ribosomes, unlike negative sense RNA viruses which need to be converted into positive sense RNA by RNA polymerase before any translation of proteins can take place.

Coronaviruses have an extremely large RNA genome with over 30,000 bases, which is highly unusual in viruses. Approximately 20,000 of these bases code for a polyprotein complex known as Replication/Transcription Complex (RTC), which unlike most other viruses with shorter genomes, has proofreading ability through an Exonuclease protein. These RTCs carry out their function in endoplasmic reticulum (ER)-derived double membrane vesicles, cleverly allowing for compartmentalization of the viral life cycle within the host cell.The remainder of the genome codes (through subgenomic mRNA transcripts) for structural and accessory proteins that coat the virus, most of which have unknown functions to date. 

Interestingly, the genome of SARS-CoV2 contains multiple proteins in one single mRNA-like positive sense RNA transcript. However, only prokaryotes are able to translate multicistronic RNAs. Eukaryotes only translate one protein per mRNA transcript. Human host cells, eukaryotes, dictate viral translation, so, how then does the virus manage to make multiple proteins from one transcript? Multiple open reading frames along the CoV2 genetic sequence allows for this. These open reading frames allow for 2 events to occur: 1) a ribosomal frameshifting event and 2) discontinuous transcription of subgenomic mRNAs that then code for structural proteins.

#4. “The Spike (S) protein on the surface of the virus binds specifically to a receptor in human cells called ACE-2, a key regulator of blood pressure in the Renin-Angiotensin system.”

The Spike (S) protein on the surface of SARS-CoV2 binds to ACE-2 before it is cleaved by the enzyme sheddase.

ACE-2 is a transmembrane metalloprotein (contains zinc and a protein base) that is found in the cells of the lungs, gastrointestinal tract, kidneys and blood vessels. These tissues are implicated in the Renin-Angiotensin system, which is a closed loop feedback mechanism that helps maintain blood pressure homeostasis. This ensures enough blood flow is running through blood vessels and tissues in order to supply cells with the necessary oxygen and nutrients for energy metabolism, which generates the ATP needed for cells to carry out their specialized functions. The following diagram explains how the Renin-Angiotensin system is relevant to COVID-19. Patients with better fitness, diets and lifestyles tend to have lower blood pressure. In fact, higher blood pressure is correlated with worse, more severe COVID-19 outcomes according to a recently published paper in Nature. This is one explanation for the wide differences in clinical severity of COVID-19.

Actually, there is currently a lot of contentious debate surrounding the role of the ACE-2 receptor, blood pressure and COVID-19 biology.

At first glance, it does not make sense for the role of ACE-2 lowering blood pressure to be a good one. After all, secreted pro-inflammatory cytokines (the messengers of the immune system) by phagocytic macrophages (the garbage collectors recruited to the site of cell death and inflammation due to viral infection), tend to increase vasodilation and capillary permeability, which in turn increases the fluid leakage (called edema) that is partly responsible for several symptoms, such as shortness of breath in the context of the lungs.  

However, it turns out that patients actually respond well to inhibitors that prevent vasoconstriction/hypertension. ACEI or ARB inhibitors, which block the ACE enzyme and Angiotensin-2 receptors on adrenal glands/blood vessels, respectively,  prevent harmful increases in blood pressure.

Upon brainstorming, I thought of a couple of mechanisms that may help explain why these inhibitors seem to be working based on research (so far):

•  Acute conditions: The body compensates for the inhibitor's prevention of blood pressure increase by reducing counterregulatory ACE-2 receptor expression on cell surfaces. In other words, the body reacts to inhibitors of high blood pressure by downregulating mechanisms that already do that since it wants to remain in homeostasis. By decreasing expression of ACE-2 on cell surfaces, there are less portals of access for the virus to enter and infect the cells, reducing its virulence. 

• Chronic conditions: The body may overexpress either ACE-2 receptors with sheddase enzyme or sheddase enzyme alone to become more sensitive to Angiotensin-2 after a significant period without contacting it (since the inhibitors given to prevent vasoconstriction reduce Angiotensin-2 production). More cleaved ACE-2 that cannot be bound by the virus spike (it only binds to intact ACE-2 receptors) may help explain the improvement in condition observed in patients after taking these inhibiting drugs.

• Conformational protein change: As described in the diagram, SARS-CoV2 can change the conformation/shape of the intact ACE-2 receptor upon binding to it when entering the cell. In this case, ACE-2 is not cleaved by sheddase and is no longer available to convert Angiotensin 2 into 1-7, which functions to lower blood pressure. This therefore keeps blood pressure high, which, as aforementioned, leads to worse prognosis (although this may still be subject to further review).

The Renin-Angiotensin system's relevance to COVID-19 may have therapeutic potential. For example, exogenous sheddase enzyme replacement therapy may provide more of the sheddase enzyme to cleave ACE-2 so that the Spike protein on SARS-CoV2 cannot bind to it and enter cells (it only binds to ACE-2 when it is in its intact conformation). Another possibility would be using the previously noted ACEI or ARB inhibitors. Notably, blocking the receptor ACE-2 (by using antibodies, for example) would be catastrophic to physiology because of the receptor’s essential role in several key pathways. The focus up to date has been mainly on the virus Spike protein for this reason. Perhaps a transient lung promoter-specific inhibitor of ACE-2 could be a potential alternative solution to fight the infection in the short term.

#5.“Clinical severity variation across COVID-19 patients may be due to differences in: 1) baseline strength of the immune system, 2) viral load and/or 3) configuration or numbers of ACE-2 receptors.” 

In the end, what makes you and me different boils down to one thing: genetics. Over time, epigenetics, the regulation of expression of genes in our DNA blueprint through methylation and histone acetylation, can additionally have a role in this effect. As one ages, these epigenetic differences accumulate and sediment. Additionally, cell damage from decades of reactive oxygen species, dysfunction in proteostasis (results in misfolded/aberrant proteins) and mutational burden weaken us as a whole. As a result of these reasons and dozens more related to aging biology, we become more susceptible to chronic health conditions that, over time, take their toll on the immune system. For instance, research has shown that leukocytes (white blood cells) responsible for fighting intracellular pathogens (cough cough, viruses) tend to decrease in numbers and function with age. In this pandemic, the need to re-interpret aging as a biological process that has targetable mechanisms is paramount. The Geroscience Hypothesis proposes that if we can delay aging itself, we could help prevent the onset of chronic disorders associated or worsened with aging, such as COVID-19.

Furthermore, another factor that may impact COVID-19 severity is the viral load, which is the quantified amount of virus particles in a host. The long incubation period may be explained by the need to reach a critical mass of viral load for disease symptom onset. Patients with more viral load may have more severe prognosis. After all, viruses replicate exponentially, not linearly, so more viruses would understandably lead to either more symptoms or a quicker onset of symptoms, although this is still up in the air. Some studies, though, have shown that milder conditions are correlated with less viral load. 

Finally, as previously described ACE-2 is the portal for SARS-CoV2 to enter human cells. Different people may genetically express more or less of these entryways for the virus on the surface of their cells. Individuals with more entryways may be more susceptible to have the virus enter their cells. The more of these ACE-2 receptors, the more sensitive a person may be to lower exposures to the virus. Therefore, they may be more at risk of infection and may accumulate a “threshold critical mass” of viral load more rapidly than someone with less ACE-2 receptors. Alternatively, minor differences across individuals in the conformation or shape of ACE-2 might make the binding interaction with the Spike protein stronger and thus more sensitive to entry.

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