COVID-19: Separating Fact from Fiction

by Anirban Mahapatra

The absence of a perfect match has prompted many to suggest that the virus was patched up in a laboratory from where it escaped. This is a controversial theory, but it cannot be formally ruled out until we find a match to SARS-CoV-2 in nature.12 But we do not need to resort to this theory of deliberate genetic engineering, when a simpler natural one exists. Some viruses such as influenza viruses and coronaviruses mix and match different genetic pieces all the time. In fact, genetic mixing is what makes influenza subtypes acquire pandemic potential. Massive reassortment of coronaviruses in bats is known to occur too. Pandemics resulting from viruses that jump over from animals occur relatively frequently.

For the cell to become available to the virus, part of the spike protein has to first attach to the receptor. Once the virus has docked to the cell, the viral package which will be used to make new virus particles needs to get inside. To do so, the viral membrane merges with the cell’s membrane, giving it access to the interior of the cell. For the two membranes to fuse, the spike protein must be split open by the host’s own cutting enzymes (called proteases). This step is crucial for infection to occur.10 Once the membrane of the virus and that of the cell have fused, the viral package is now ready to enter the naïve cell and subvert it to make the parts needed to create new virus particles. How does this occur? As I mentioned, it’s quite ingenious because RNA can serve as both the genetic blueprint and also the basis for the creation of viral proteins. The machinery inside the cell that typically makes cellular proteins takes the RNA and makes a large string of amino acids called the polyprotein. Certain proteins known as proteases act as cleavers. When they see a pattern of amino acid building blocks of proteins that they recognize, they make cuts. The viral polyprotein isn’t functional, until it is cut at specific places by a cutting enzyme called the viral main protease. These smaller functional pieces, including the RNA copier enzyme, can now make more copies of the genetic material. Think of it this way. You have a mechanical loom that can make a designed fabric bas...

In contrast the wealth of information on SARS-CoV-2 entry into cells, not much is known about how fully formed virus particles exit cells. Unlike most other enveloped viruses that use the cell’s biosynthetic secretory pathway to get out, SARS-CoV-2 and a few other coronaviruses use lysosomes—parts of cells that normally compact trash.12 In the process, virus particles wreak havoc on lysosomes, preventing them from performing their job of clearing out other invaders and broken cellular parts. It takes around ten minutes for SARS-CoV-2 proteins and RNA to get inside lung cells. It takes much longer, approximately ten hours, for new virus particles to be made inside the cell. Anywhere from a few hundred to a few thousand virus particles might come out from one infected cell.

A virus is a like a thief going from one house to another with one key, trying to see what it can open with it.

A snug fit by the receptor-binding domain and the commandeering of widespread human cutting enzymes called proteases (including one called furin) to cut the spike protein contribute to making SARS-CoV-2 highly infectious. Taken together, a range of factors explain why the virus shows up in so many different cells and in so many unexpected places inside the body compared to other coronaviruses.

The concept of preventing the virus from getting inside a cell is simple. If we can stop the ‘key’ (spike protein) that the virus uses from ever finding the ‘lock’ (ACE2 receptor) by attaching something else to it (drug or antibody), we can stop the virus from ever infecting the cell. Antibodies that bind to the spike protein form naturally in people who recover from infection and should protect these people from a second infection for some time. These are neutralizing antibodies and they are exactly the kinds of antibodies generated by effective vaccines as well.

Instead of trying to block the spike from binding to the ACE2 receptor, some researchers have taken a different tact altogether. They are experimenting with creating decoy ACE2 that the virus sticks to instead of actual cellular ACE2 receptors that let it inside cells.25 A drug company is using this strategy in the hope that flooding the body with soluble ACE2 receptors will fool the virus into attaching to it, instead of to the ones on actual cells. The goal here is to saturate virus particles with something that renders them ineffective in infecting cells.26 A similar strategy has shown great promise in blocking HIV infection in a laboratory setting.27 Yet another approach is to block the cell’s own ACE2 receptor so there’s less of it for the virus to grab on to. As an analogy, this can be thought of as filling in a keyhole so that the key doesn’t work any more. The problem is that the lock (ACE2 receptor in this case) has a biological function within the body. Disrupting the ACE2 could have unintentional side effects. I mentioned that the virus needs the spike protein to be cut for infection to occur and this is done by host proteases. Removing the cellular proteases that SARS-CoV-2 manipulates to cut its spike protein is another way to design drugs. But here also, we need to be careful. Blocking proteases to prevent viral entry could also have unintentional side effects. Still, TMPRSS2 might be a reasonable drug target compared to furin. Thwarting this protease during ...

By infecting a host cell that has an ACE2 receptor, SARS-CoV-2 causes it to sound the alarm to nearby cells. The host cell does this by undergoing a kind of programmed cellular suicide. The signals released are its swansong: they’re recognized by nearby cells, which generate signalling molecules called cytokines. Then, these new signals call in the immune force—monocytes, macrophages and T-cells to the site of the infection. In a healthy immune response in most people, the virus-specific T-cells are attracted to the site of infection where they eliminate the infected cells before the virus spreads. Antibodies block viral infection. All the neutralized viruses and dead cells are recognized by alveolar macrophages, which clear them out. There’s minimal and reversible damage to the lungs. Patients with functional immune systems and without obvious risk factors can generate healthy immune responses that quash the virus before COVID-19 progresses to a severe phase. In a dysfunctional immune response, cells build up in the lungs without being cleared. This causes many cytokines to be produced and they turn on lung infrastructure, thereby causing destruction. These cytokines also circulate to other organs where they can cause multiple organ damage. If there are antibodies that cannot neutralize the virus, they can boost infection instead of warding it off. The sea of cytokines released by the immune system results in something called the ‘cytokine storm’.11 An abnormally low lymp...

For several different RNA viruses, viral RNA persists long after the infectious virus can’t be found within the body. It is not unusual for SARS-CoV-2 RNA to be detected even six weeks after the first positive result. This is viral debris.

An antiviral can work on any of the steps of infection but is most effective early in the disease cycle. In contrast, drugs that control abnormal immune responses and inflammation (resulting from viral infection) in certain patients work well later as the disease progresses. The disease progression of COVID-19 doesn’t only involve viral infection and replication which would be treated by an antiviral, but also includes problems with immunity and inflammation in those who develop serious disease. So, a combination therapy with anti-inflammatory drugs in addition to antivirals may, in theory, be effective. Drugs that modulate cytokines such as interleukin-6 are also being tested. In addition, those who have blood clots might be prescribed anticoagulants.

However, use of steroids as anti-inflammatory therapy has a specific usefulness: inhibiting cytokines and carpet-bombing the immune response are not things we want to do when there is a chance of other infections.

An example of an inactivated vaccine is Covaxin which was created in India by the National Institute of Virology of the Indian Council of Medical Research, and Bharat Biotech. Thousands of participants were being enrolled for a Phase III clinical trial in late November 2020.16 Other vaccines can be made from protein parts of viruses or virus-like particles, all of which are deficient in some key component present in an infectious virus. Some of these also require adjuvants to fire up the immune system. A few vaccines consist of virus proteins packed into nanoparticles and injected into the body. These virus proteins are recognized as alien by the immune system which starts to mount an appropriate response. By the end of 2020, Novavax had enrolled patients in Phase III clinical trials for their version of this kind of vaccine.17

But by the end of 2020, the vaccines that had generated the most excitement used RNA. An RNA vaccine skips the first few steps of a DNA vaccine entirely and induces potent immunity.18 Once inside the cell, it is translated directly into the spike protein which is used by the host cell to build up immune responses. By the end of November, two leading candidate vaccines created by Pfizer and BioNTech and by Moderna that used RNA technology had been shown to be effective after two doses. In December, these candidates were the first two mainstream vaccines approved in the world. The broad use of mRNA vaccines may signal a paradigm shift in how we try to prevent the spread of infectious diseases.

Why are the first approved RNA vaccines only available now? After all, they could’ve helped us to combat other infectious diseases in the past. Three recent technical advances make these vaccines possible. First, RNA is unstable and difficult to get inside cells. But by encasing it in molecules known as lipid nanoparticles, delivery and stability have been improved. Second, ‘foreign’ RNA can trigger an immune response (instead of the protein that it helps the body make). But if the RNA is chemically made with synthetic nucleosides, then the immune system doesn’t react against it. Third, RNA is ‘read’ by the host cells to make viral proteins. But before it was modified and stable, it was not read well. The proverbial stars aligned shortly before the COVID-19 pandemic.

The last class of vaccines I want to discuss contain a DNA blueprint inserted into the shell of a harmless virus (usually an adenovirus vector).21 This is quite ingenious in that it uses a defective virus to deliver a message that will generate antibodies to SARS-CoV-2. These defective viruses generate immune responses but are either too weak to cause disease or are missing the necessary components to replicate altogether. In 2020, AstraZeneca, in conjunction with Oxford University, and Johnson & Johnson were two companies that had enrolled thousands of participants in trials of vaccines that use adenovirus vectors. By late 2020, the AstraZeneca candidate vaccine had shown promising, initial results and was poised for approval for use in 2021.