Covid-19Health

IN THE BOXING RING WITH COVID-19: How do we fight a virus?

Grace En Xie1

Abstract

The COVID-19 pandemic is the ongoing battle between humans and the virus SARS-CoV-2. SARS-CoV-2 attacks by infiltrating the human body, causing mild to deadly effects. The virus spreads through human transmission into the lungs, activating the immune system to help or harm. People around the world have worked to reduce SARS-CoV-2’s effect through quarantining, social distancing, and wearing face masks. However, are these the only strategies for fighting COVID-19? Scientists, researchers, and governments have teamed up to develop different treatments to stop the spread of the virus by targeting its weaknesses. In this article, 3 methods are described: vaccines, chemicals (Remdesivir), and steroids (dexamethasone). Vaccines have been developed to teach the body to fight the virus, and drugs are used to stop the virus’s effects. Remdesivir is said to decrease the recovery time of COVID-19 patients, and dexamethasone uses immunosuppression to save patients by preventing cytokine storms. However, dexamethasone and Remdesivir are not formal treatments, so prevention is the best strategy to fight COVID-19.

Introduction

SARS-CoV-2, COVID-19, and coronavirus are words that appear every day in the news, at school, and in daily conversation. What do these words mean and why are they important? COVID-19 is a disease from an infection of SARS-CoV-2. SARS-CoV-2 is a virus of the Coronaviridae family, whose viruses all have a crown (corona) made of spikes that project out of the viruses’ surfaces. Coronaviruses typically infect humans and mammals with symptoms that resemble the common cold, but they can also cause more severe symptoms including respiratory difficulties, nerve problems, and digestive disorders. In addition to SARS-CoV-2, other coronaviruses such as SARS-CoV and MERS-CoV have previously caused outbreaks. However, these did not reach the unprecedented levels observed for COVID-19 with 38 million infected and 1 million people dead since December 2019[1]. SARS-CoV-2 is infectious and deadly because of the virus’s mechanisms and how they affect the human body. Scientists around the world are finding ways to combat SARS-CoV-2.

Infection and Spread

SARS-CoV-2, like all viruses, is incapable of producing multiples of itself. Hence, the virus invades other organisms’ cells and hijacks the host’s replication system. The invasion plan begins when homing devices on the spikes of the viral surface lodge onto the ACE2 (angiotensin-converting enzyme 2) receptors of host cells present in the lungs and small intestine. These ACE2 receptors act as doors allowing materials in and out of the cell, but the virus tricks the receptor into letting it enter the cell. Once inside, the virus releases its genetic code (RNA molecule) and makes a copying machine (an enzyme called RNA-dependent RNA polymerase (RDRP)) by using the host’s energy and materials to reproduce more viral RNA. The virus then packages the newly made RNA with outer coats to make progeny viruses, which rupture the host cells to disperse and infect other cells in the surrounding tissues[2].

A person afflicted with SARS-CoV-2 can infect others with the virus when they sneeze or speak, releasing respiratory droplets loaded with virus particles, which enter the body through the nasal passageway, unhealed wounds, or exposed mucous membranes lining the mouth and eyes. The host’s immune system normally detects and annihilates invading viruses by telling the body to produce molecules (cytokines) that activate immune cells, resulting in inflammation that manifests as fever and cough. If the immune system is frail, such as in the elderly, these viral invaders can easily overpower the weak defences.

Lethality of SARS-CoV-2

If the infection cannot be fought off, COVID-19 can progress into acute respiratory distress syndrome (ARDS), severe cardiac complications, kidney failure, and death. Critically ill patients require intensive care, often needing ventilators and emergency medicine to keep them alive. When an exceedingly large number of severely ill patients succumb to the disease at the same time, the public health system is overwhelmed. The large influx of patients can cause hospitals to run out of crucial resources such as beds and ventilators, leading to more deaths that could have otherwise been preventable.

Cytokine storm—an over-reacted immune response

A major contributor to ARDS is a phenomenon known as “cytokine storm”. For reasons still unknown, the immune system can sometimes overreact to infection by overproducing cytokines that trigger widespread inflammation throughout the body. An overactive immune response can lead to the destruction of multiple internal organs and mortality.

Weapons to fight COVID-19

  1. Vaccines

Scientists, doctors, and researchers have determined two things that could help end the pandemic and bring back normal daily life: vaccines and treatments. Currently, vaccines for SARS-CoV-2 are made using a live virus, inactivated virus (“dead” virus), viral vector (proteins of the virus), subunit (fragments of viral proteins), or nucleic acid (part of viral genetic code). More than 120 vaccines are currently being developed by companies, governmental agencies, and universities. Plans to accelerate the vaccine development process are underway[3].

By exposing the human body to various parts of the inactivated virus, vaccines prepare the body to detect and kill the virus via ‘teaching’ the immune system to remember how to make antibodies against the specific virus. If the vaccines are effective, people can produce antibodies to counter the virus and restrict its spread. One important target of the SARS-CoV-2 antibody is to obstruct the binding of the viral spike protein to the ACE2 receptor, preventing viral entry into host cells[4] (Figure 1A).

However, there are drawbacks to this strategy. First, no previous vaccines have been successfully made against SARS-CoV and MERS-CoV because these vaccines did not pass the initial phase of testing. As a result, there is a lack of scientific data available to serve as a stepping stone to enhance the likelihood of producing an efficacious SARS-CoV-2 antibody. Furthermore, the rapid mutation rate of the virus nullifies the usefulness of the vaccines.

  1. Terminators (inhibitors) of viral genome replication

As of October 20, 2020, there are no approved treatments for COVID-19. Supportive care such as antibiotics, antifungals, oxygen support, alternative medical (for example herbal) treatments, and in extreme cases, drugs still under trial may be employed. The development of treatments is currently still an ongoing process of testing whether drug candidates used for treatment of other viral diseases are effective against SARS-CoV-2. For example, a drug called Remdesivir, which was originally made to treat the Ebola virus, is now ‘repositioned’ to stop the multiplication of SARS-CoV-2 virus.

Remdesivir was found to combat SARS-CoV-2 by preventing it from replicating. Remdesivir is a chemical that resembles a nucleotide, the building block of the viral genomic RNA. When making copies of the viral RNA, the RDRP enzyme is unable to differentiate between these building blocks and Remdesivir, allowing the latter to be incorporated. Once integrated, Remdesivir will change the contour of the RNA to halt further RNA genome duplication by the RDRP[5] (Figure 1B). Remdesivir has also been found to be effective against MERS-CoV and SARS-CoV.

Even though it is not a formal treatment, Remdesivir is allowed to be used in emergencies as it has been reported to accelerate the recovery of COVID-19 patients. However, the results have been inconsistent with tests conducted in separate localities, showing little help to prevent death[6].

  1. Extinguisher of ‘cytokine storm’

A clinical trial code-named RECOVERY conducted in the United Kingdom by a group of scientists reported that the drug dexamethasone can surprisingly save about one in three critically ill COVID-19 patients[6]. Dexamethasone is a safe and commonly used man-made steroid (glucocorticoid) that suppresses overactive immune responses during the ‘cytokine storm’ (Figure 1C). Dexamethasone treatments do not directly affect coronaviruses, but rather modulate the host immune system especially in patients who suffer from overstimulated immune systems and are typically placed on life-supporting ventilators. Immunosuppression in this case is a double-edged sword, as the immune system is also essential in counteracting the viral invasion, especially at the start of the infection. Scientists found that the timing and dosage of dexamethasone need to be fine-tuned to prevent early or extreme dampening of the immune response. Dexamethasone is the first drug that has shown optimistic results in significantly reducing the deaths of COVID-19 patients.

As more research and testing are performed, the possibility of an effective cure against COVID-19 increases. Vaccines and treatments in development have promising success rates in humans. The knowledge gained from developing weapons against COVID-19 allows the world to prepare for future diseases.

Figure Legend

Figure 1: Infection pathway of SARS-CoV-2, the COVID-19 virus, into the human lung and the drugs used to combat the virus attacker. (A) The virus’s entry via binding to an ACE2 receptor. (B) After entry, the virus injects its RNA genome into the host cells to replicate and multiply into more progeny viruses. (C) The human body produces cytokines to activate the immune system, which induce inflammation and the killing of the virus. However, if overdone, the result is a condition called cytokine storm that can cause the destruction of internal organs. Viral entry in (A) can be treated with vaccine antibodies, and viral replication in (B) can be impeded using a nucleotide analogue such as Remdesivir. Cytokine storms and dysregulated immune systems can be tuned down using the steroid dexamethasone, as shown by the Recovery clinical trial.

In the boxing ring with COVID-19—who wins, who loses?

When will wearing masks not be mandated? Will life return to be the same as before the COVID-19 pandemic? These are questions asked every day as people long for the pre-COVID-19-pandemic freedom. With so many weapons developed to counter COVID-19, are humans able to defeat the disease? Unfortunately, the answer has yet to materialize in the foreseeable future.

Conclusion

There are currently no effective anti-COVID-19 drugs approved for general public use. Although expectations have been placed on vaccines, research has shown that the virus is fast mutating. It is possible that the virus may be mutating too quickly and that it may overcome the vaccines’ effectiveness.

As of now, prevention is the best strategy against COVID-19. Thus, it is important to practice social distancing, wear masks, and quarantine upon testing positive for COVID-19. Prevention techniques may make it possible for life to adjust to a ‘new normal’. The fight against COVID-19 is a journey and constant vigilance must be practised. Defeating the virus must be a collective effort where everyone, including kids, has a role to play. If everyone takes responsibility and gives up personal freedoms to protect others (the World Health Organisation dubbed this as ‘solidarity’), victory against COVID-19 will be near.

Glossary

Receptor: A molecule on the surface of a cell that can be stimulated by substances from its surroundings to control the response of the cell to its environment.

RNA-dependent RNA polymerase (RDRP): An enzyme that makes copies of RNA, which also includes the genome of the SARS-CoV-2 virus.

Cytokine: Molecules secreted by some cells in the immune system to activate other types of cells to help defend against invading pathogens.

Inflammation: Body symptoms arising from killing invading pathogens by white blood cells of the immune system.

Cytokine storm: An abnormal condition in which the immune system becomes over-stimulated by cytokines, resulting in the host’s immune system attacking its organs.

Acknowledgments

I thank Mei Gordon-Washington, Lois Tian Xie, Di Xie, Chin Yip Han, and Sarah Tang Shuwen for critically editing the manuscript. Special thanks to Professor Ee Sin Chen for his guidance and mentorship.

References

[1] “COVID-19 Map.” Johns Hopkins Coronavirus Resource Center. Accessed July 15, 2020. https://coronavirus.jhu.edu/map.html.

[2] Hartenian, E., Nandakumar, D., Lari, A., Ly, M., Tucker, J.M., and Glaunsinger, B.A. 2020. The molecular biology of coronaviruses. J. Biol. Chem. 259:12910-12934. doi: 10.1074/jbc.REV120.013930. https://www.jbc.org/article/S0021-9258(17)49954-6/fulltext.

[3] Poland, G.A., Ovsyannikova, I.G., Crooke, S.N., and Kennedy, R.B. 2020. SARS-CoV-2 vaccine development: current status. Mayo Clin. Proc. 95:2172-2188. doi: 10.1016/j.mayocp.2020.07.02. https://www.mayoclinicproceedings.org/article/S0025-6196(20)30827-2/fulltext.

[4] Wang, Y., Liu, M., and Gao, J. 2020. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc. Natl. Acad. Sci. USA 117:13967-13974. doi: 10.1073/pnas.208209117. https://www.pnas.org/content/117/25/13967.full.

[5] Eastman, R.T., Roth, J.S., Brimacombe, K.R., Simeonov, A., Shen, M., Patnaik, S., and Hall, M.D. 2020. Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent. Sci. 6:672-683. doi: 10.1021/acscentsci.0c00489. https://pubs.acs.org/doi/10.1021/acscentsci.0c00489.

[6] Cain, D.W., and Cidlowski, J.A. 2020. After 62 years of regulating immunity, dexamethasone meets COVID-19. Nat. Rev. Immunol. 20:587-588. doi: 10.1038/s41577-020-00421-x. https://www.nature.com/articles/s41577-020-00421-x.

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