understanding

Physician Madhu Sanjanwala has sent this article, co-authored with Elizabeth McNeil, to India-West in the hopes of educating the Indian American community about the recent outbreak, their contributions and science behind the fight. Seen above is a healthcare worker wearing a face mask at UCLA Emergency on March 24, 2020, in Los Angeles, California. (Frederic J. Brown/AFP via Getty Images)

Our genome consists of genes in 23 pairs of chromosomes. Genes are made up of the basic building blocks of deoxynucleic acids (DNA) joined to one another. Thousands of genes are scattered on the 23 pairs of chromosomes. When a gene is activated, it produces a temporary replica made up of ribonucleic acids (mRNA), which then produces proteins. Proteins are the real molecules that carry out a particular action or a biochemical reaction. As soon as the protein is produced, the mRNA is destroyed: the mRNA is transient or short lived. This is like the hard drive and the random-access memory in computers. The hard drive contains information brought into the memory with which we then work. Once we are finished, having achieved our final product, we close the program. At that time, the memory is flushed.

However, most viruses differ in this regard, since they are pieces of RNA protected within a shell of proteins and a lipid layer. These proteins not only protect the virus; they also help propagate in our system by binding to specific proteins on some cell types, such as, for example, lung and blood cells.

How does the immune system work?

Our bodies have naturally evolved to fight off complex foreign entities, such as bacteria, viruses, pollens, yeasts, and other biological agents. In addition, our bodies also see as foreign some small molecules, which are simple entities. Foreign materials entering the body are called pathogens. Complex pathogens take advantage of our physiological resources and multiply, making us very sick. In general, bacteria double every 8 hours, while the rates of multiplication of viruses vary. Some viruses multiply rapidly. The rate at which they multiply directly correlates to the severity of the illness they can cause.

If a virus multiplies quickly and can transmit quickly, we call it virulent. The recent novel coronavirus that is creating havoc falls into this category. Complex pathogens, which are quite evolved, secrete proteins and other chemicals that interfere with the functioning of the human biological system. Sometimes, all that is needed is one particle of virus or bacteria to enter the body. Once in the system, the body provides all resources the virus or bacteria needs to survive and multiply.

Pathogens enter our bodies by different routes, such as nose, eyes, mouth, genital areas, skin, etc. For this reason, it is very important not to touch your nose, eyes, or mouth if you are in an environment that contains droplets of viruses or bacteria.

The human body’s typical response to these pathogens depends upon many factors. First and foremost is whether the person has encountered the pathogen before or if it is unknown/new. For all of us, the recent coronavirus is new. No one has been exposed to it before; hence, we call it a novel virus.

If we had been previously exposed to the pathogen, our body would recognize it and our immune system would initiate physiological mechanisms to combat it. The immune response in such a case would then be extremely mild, with a day or two of tiredness. An affected person would start feeling better soon, cured of infection, thankful that nature had built in this effective memory system.

This is also exactly how vaccination works. Once we are vaccinated, the immune system is primed to recognize the pathogen against which the vaccine was developed. Specific immune cells are very low in number before the vaccinated body is attacked by the pathogen, but as soon as the invading pathogen is recognized, the specific immune cells start to multiply and amplify to take down the pathogen.

When, however, a pathogen is brand new – in other words, when the human body has never encountered it before through illness or vaccination – the body has no immune cells with which to fight it. As a hypothetical example, let us assume that a new pathogen is an influenza virus. The body has never seen this virus, so the immune system starts working. First is the B-Cell response. B-Cells produce antibodies to attack the virus. The way they do this is comprehensive and magical. The antibody-producing machinery is designed to produce a perfect or near-perfect fit to the pathogen.

Let us give a hypothetical shape to our imagined pathogen (the shape of a pathogen remains the same even when it multiplies). Let us say this shape is a rose. (Keep in mind that real roses are of different sizes, colors, fragrances, etc.) In reaction to the pathogen, the immune system works to collect different parts of genes to make an antibody that will match the mirror image of the rose shape. The genes for producing these antibodies are located on chromosomes 2, 14, and 22. The human body produces five types of major antibodies: IgM, IgG, IgE, IgA, and IgD.

Each antibody type is characterized by a constant part, which is derived from chromosome 14. If you have seen a simplified diagram of an antibody, it is “Y” shaped. The actual structure of the antibody also resembles the “Y” shape. The stem of the “Y” is constant in a given antibody type. What is different is the “V” on top of the stem, which is called a variable region. The constant region is called the “heavy chain” and the variable region the “light chain.”

The variable region, derived from chromosomes 2 and 22, is designed to fit the specific invading pathogen. Our immune system produces thousands of antibodies, each differing in the variable region – the “V” part of the antibody or the light chain. One from these random thousands of antibodies will be a perfect fit for a given pathogen. This is like a lock and a key. The immune system produces thousands of keys for a lock, but only one can open it – the one that fits perfectly. Once the perfect fit is identified, the constant part of the antibody, the stem of the “Y,” sends a signal to the B-Cell to announce a perfect fit. The B-Cell that produced this perfect fit now multiplies, producing more and more of the desired antibody. These antibodies are released into the bloodstream to find the pathogen wherever it is hiding.

Once the body has enough of the antibodies, they bind to the pathogen and interfere in the pathogen’s reproduction. This entire process of identifying, making a perfect fit, and mass production of antibodies takes about 4 to 8 days. We feel sick for that long, and most of the common mild sicknesses go away in that time frame.

The first antibody type we see is the type “M”; hence, we call these IgM (Immunoglobulin M). During the antibody production process, the body also makes another type of antibody, called IgG (Immunoglobulin G), which is more permanent and fine-tuned than IgM. At this stage, the body keeps this antibody-producing cell as a reserve in memory. If we get exposed to the same or very similar pathogen, our immune system now knows how to attack it without wasting 4 to 8 days of identifying and making a perfect fit; the immune system mass produces antibodies so that the pathogen has no opportunity to cause damage. Since the entire process is highly specific – identifying and building antibodies for a pathogen – the immune reaction is also pathogen specific.

Remember that, earlier, we created the antibody response to one specific imagined pathogen shape – a rose. When one of the petals of this imagined rose shape is bigger or of a different color, the immune system will react to this similar, but not the same, shape. Because of what the immune system has accomplished, above, most of the work has already been done in identifying a rough shape, but the system now must go through the matching process again to mirror this similar shape – a fine tuning. This is similar to how the body reacts to the cold virus (influenza) to which we are exposed year after year. The virus is similar each year, but because it has slight changes (mutations), we become infected again. However, our body recognizes what, in general, the virus looks like, and so goes to work to mitigate the pathogen by producing a better (a more fine-tuned) V-shaped variable region of the antibody. This results in our feeling sick for some time but getting better on our own.

While the body builds immunity to a known pathogen, another arm of the immune system is also activated. This arm, the humeral system, is comprised of another subset of blood cells called T-Cells. Like B-Cells, the T-Cell arm is involved in building memory related to a given pathogen. Combining responses of immunoglobulin cells and the humeral system, we are well protected. At times, we get infected but do not even show any symptoms; without us knowing, the body gets rid of the pathogen.

In addition to the above immune response systems, other cells, such as macrophages and neutrophils, help to kill pathogens, too, by engulfing and internalizing them in a process known as phagocytosis.

COVID-19

The above is an overview of the immune system. Now we switch our focus to the novel coronavirus COVID-19. “Co” stands for coronavirus, “vi” for virus, and “d” is disease. Since it was identified in 2019, it was named COVID-19.

Microscopically, the virus looks as if it has spikes all over it. On the viral surface are four essential proteins: S, M, E, and N proteins. Like most viruses, COVID-19 is made up of small pieces of RNA surrounded by lipids (fat that is insoluble in water) and proteins. The lipid layer and the proteins protect it from decaying. It has been speculated that this virus can survive on solid metal surfaces for days, and for a few hours on clothing and in the air. When an infected person coughs or sneezes, the viral particles become airborne. Also, when the infected person touches anything, the viral particles are transferred to the items the person touches. The protective lipid layer is water insoluble, so the virus will not be destroyed by washing one’s hands with water only; the lipid layer is destroyed by soap that exposes the viral RNA. The RNA is destroyed by a protein called Ribonuclease (RNase). RNase is everywhere, and it chews up RNA in an instant if the RNA is unprotected. When you have greasy pans or hands, what takes the grease off is soap and warm water. In the same way, the virus has grease (lipid layer) that can be dissolved by soap killing the virus.

If the virus is left intact and then inhaled, it enters the respiratory system and binds to a protein on the cell surface of blood cells that is familiar to many of us: the ACE-2 (Angiotensin Converting Enzyme 2) protein. ACE-2 in implicated in regulating blood pressure. Many of us take blood pressure medications that are ACE inhibitors; they bind to the ACE-2 protein on the blood cell surface. COVID-19 likewise binds to the ACE-2 protein, and when it does, it is internalized in the cells. The cells have all the raw materials needed for the virus to grow and multiply. The viral particles are then released from the infected cells and bind to other cells, and the cycle continues, eventually paralyzing the blood immune cells. The viral particles are increased to a high level, which is referred to as viral payload. The greater the viral payload, the more severe the reaction.

If someone’s immune system is already compromised by other underlying issues or prevailing infection, then the entire system is overwhelmed, and the disease is difficult to control. This leads to lung inflammation and the lungs’ filling with mucus. When the lung alveoli surface is coated with mucus, exchange between blood and oxygen is affected. The capacity of alveoli to hold air (thus, oxygen) is compromised due to the loss of the air pockets that are now filled with mucus. This results in the blood’s inability to supply the oxygen needed for all other organs. We then feel sick and fatigued. In severe and critical cases, the situation ends up in a tragedy.

What makes COVID-19 so uncontrollable is its ability to infect us, to multiply infection in many of our cells. Eventually, we infect other people. A few days after exposure, a person starts showing symptoms like dry cough, runny nose, fever, fatigue, and chills. In people with compromised immune and respiratory systems, shortness of breath can then lead to hospitalization.

Some unsubstantiated reports asked people to evaluate the use of ACE inhibitors; overall, however, the medical community has strongly urged people to continue taking the medication. Not taking your medication could create other undesired effects. It is best to consult your physician.

Most other viruses show symptoms first and then become infectious. COVID-19 is different in that regard. It is asymptomatic for days. It infects us, then others, and only then do the delayed symptoms manifest. This highly unusual behavior, which has not been seen with other viruses, has allowed the virus to spread silently to many people. This is the reason why testing for COVID-19 is critical, so that infected people can then quarantine to stop the virus’s rapid and silent spread.

Another scary aspect of COVID-19 is that it grows exponentially in our system, which means it also mutates quickly. Infected individuals should develop permanent immunity to the virus once the infection is over; however, if COVID-19 mutates drastically, as influenza does, we may lose immunity when this coronavirus comes back every year in a different form. A re-emergence of this virus may prove to be dangerous, which is another reason we all must do our part in controlling it now.

What is being done? 

Vaccines

First, what are vaccines, and are they safe? A vaccine is a process in which we take a fragment of the pathogen – an antigen – and inject it into the body. The fragment we choose is readily available on the surface and is most often a functional part of the pathogen. Its introduction raises the immune response to the injected fragment. The immune system is now primed to attack that part of the live pathogen if the body is ever infected with it. Vaccines are usually safe. People are afraid of vaccination because of perceived side effects. Reaction to a vaccine is not due to the antigen, however, but to the ingredients (adjuvant, stabilizers, preservatives, etc.) used in the development of the vaccine. Most of the time, the reactions are mild and go away in few days. When the risk is weighed against the rewards, the rewards are much higher.

The process of developing a vaccine is rather straightforward but can be challenging in some cases. The way the vaccine is developed is through identification of the pathogen’s unique areas – epitopes – that can be attacked. For example, in COVID-19, the aforementioned S, M, E, and N proteins are ideal epitopes. These proteins are unique, and hence we develop similar proteins that can simulate the natural viral proteins and use them to induce an artificial reaction. Sometimes, we use fragments of proteins. This potentially leads to a vaccine that will cause immune reactions in the body, mimicking the virus, and thus producing immune system memory as described earlier.

When the memory system is built, any invasion of the live virus will be taken care of by the body’s own immune system. Acquiring immunity takes about 8 to 15 days. This is the reason that, when we are inoculated with the vaccine, we feel uneasy for couple of days: our immune system is gearing up to ward off the mock infection. When the actual virus now attacks us, our immune system will identify these epitopes, destroy the proteins on the viral surface, and render the virus incapable of growing. We are now saved from the aggressive and virulent effects of the virus. If we are saved by killing the virus on entry, the virus does not propagate, and we do not infect others. The spread of the virus stops, and we are all happy.

Another type of vaccine that is developed uses the T-Cells (see the humeral system discussion above) from survivors and exploits the mechanism to build the immunity.

Additionally, RNA vaccines use the portions of the pathogen’s RNA to develop vaccines that prime our immune system to identify the RNA of the virus, attack it when it infects us, and disable it at its roots.

Many times, a cocktail of different approaches may be necessary to induce and acquire desired results. This particular virus may necessitate a multi-pronged approach with a cocktail vaccine.

With respect to COVID -19, we have heard that the vaccine developed by a company called Moderna, in collaboration with the National Institutes of Health (NIH), has been administered in volunteers. The first phase is to determine whether the person can tolerate the vaccine. The next phase is to allow the person’s immune system to react to it and develop an immune response. This, as we discussed, takes 8 to 15 days. After that time, the person’s blood is drawn and tested to see if it contains antibodies to the part of what was used to create the vaccine. Then the specificity is tested. Next, the blood is then tested to see if the antibodies bind to the viral particles. If viral growth is arrested, we have a winner. If not, then we must look at other vaccines and epitopes. Once the vaccine is identified as effective, then it is scaled up to make sure that the integrity and specificity is maintained. More healthy volunteers are tested to ascertain the vaccine’s ability to combat the attack of live virus. This process takes 2 to 3 months. Next is the scale-up to produce the vaccine in mass. All tests are done to ascertain the vaccine’s effectiveness after it is mass produced. This consumes another 2 to 3 months. Thus, the timeline for a successful vaccine candidate is, at best, about 6 to 9 months.

Other companies are attempting to develop specific vaccines, including the German-based CureVac and BioNTech. Pfizer has agreed to collaborate with BioNTech, which is ahead of the curve, and CureVac will begin testing in early summer. These companies specialize in RNA vaccine technology. Other companies with wider research and development agendas, such as Johnson and Johnson, also now have active vaccine development programs.

China announced recently that they have identified a successful vaccine candidate and will begin trials in a matter of weeks. With combined efforts all over the world, we hope to have a successful vaccine in a timely manner. We must hope that the virus does not mutate drastically anytime soon, however. Otherwise, we may lose specificity, reducing or rendering useless the vaccine’s protective power.

SARS and MERS, other coronaviruses that caused alarm several years ago, have taught us much about both these viruses and the attempts to vaccinate against them. For a comprehensive (and highly technical) recent review of SARS and MERS vaccine development attempts, see https://www.frontiersin.org/articles/10.3389/fmicb.2019.01781/full.

Treatment

Treatment for the disease caused by this novel coronavirus has been limited, since COVID-19 attacks the respiratory system in such a drastic manner. Fortunately, however, research and treatments for HIV, Ebola, SARS, and other viral diseases are helping to develop effective COVID-19 treatment protocols.

HIV and Ebola drugs from Abbvie and Gilead have shown promise in treating the COVID-19-induced illness. Gilead’s Remdesivir, developed to treat the Ebola virus, is currently being used in several COVID-19 trials in China, the results from which are expected in mid-April.

Abbvie’s products Opinavir and Ritonavir also have shown positive results in a limited number of patients. These drugs essentially destabilize proteins on the surface of the virus. Regenron has announced a program to develop monolconal antibodies to treat infected patients. Of all treatments, the antibody approach may offer the greatest promise.

In addition, a long-known anti-malarial drug, Chloroquine, has the potential to mitigate the severity of the disease. Clinical trials are underway to determine its efficacy.

Isolating plasma from the survivors and infusing it into severely ill patients is another successful approach. Survivors have developed antibodies to the virus, which then circulate in their bloodstream to slow down the viral replication.

In the coming days, results from all these approaches should be available to help narrow down and treat the disease in severely affected patients.

Preventing the spread of COVID-19

Global and local authorities have learned from China that the best way to control the spread of the virus is to contain it in a limited population. Also, temperature affects the life of COVID-19 on solid surfaces. Temperatures of over 780 F reduce the life of the virus on solid surfaces dramatically – from hours and days to minutes. With the approaching summer, the viral spread may come under control. However, if the virus continues to remain active in limited people, it may start a subsequent phase in fall and winter. So, it is advisable for all of us to comply with the request from authorities to minimize spread.

We must do our best to control and defeat COVID-19. I suggest keeping disinfectant handy when you go to stores and while pumping gas. Wipe the cart handle with disinfectant before touching it and after you are done, for the next person. Similarly, wipe the gas pump handle to keep yourself and others safe. People are the most careless regarding these two places, each of which provides a perfect vehicle for the virus to transmit.

Washing your hands with soap is the best way to keep virus free. The same applies to any surface.

There have been suggestions not to use ibuprofen, as it may worsen COVID-19 outcomes. If you get infected, let the virus take its course. Isolate yourself to avoid spreading the virus. Take acetaminophen to reduce fever and pain, if necessary. Inform and stay in touch with your physician during the sickness. Follow guidelines from authorities and your physician. If you start to experience shortness of breath, contact a physician ASAP.

There is no need to panic. Stay calm and positive. Take all precautions possible not to become infected or to spread the virus. China’s drastic quarantine measures paid off to curtail the spread of COVID-19. Similarly, the virus spread in South Korea was controlled by testing people with infection and quarantining them. In the US, we have already seen some optimism in containment of the spread with California’s “Stay At Home” order. New York, Illinois, and other states are following a similar containment path. We have proof that quarantine works, and it will if all comply. We will overcome this disease if we all work together.

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