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9 February, 2021

Covid-19 Infection: The Key is in the Immune System

Dr. Arianne Ferrini, Imperial College London

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COVID-19 identikit

Coronaviruses (CoVs) are a large family of viruses that cause respiratory and intestinal diseases in humans and animals (Tizaoui et al.). Coronaviruses typically cause mild colds in humans. However, the epidemic of Severe Acute Respiratory Syndrome (SARS) in China in 2002 and the Middle East Respiratory Syndrome (MERS) in the Arabian Peninsula in 2012 showed that they can also cause severe illnesses. 

A novel coronavirus called SARS-CoV-2 was first identified in China at the end of 2019. This was a strain that had never been seen in humans before and became responsible for the current Coronavirus Disease outbreak (COVID-19). 

SARS-CoV-2 causes an acute respiratory syndrome characterized by cough, difficulty breathing, high fever, muscle pain, and other flu-like symptoms. These symptoms can range from mild (or no symptoms at all) to severe illness (Machhi et al.). 

COVID-19 structure

Coronaviruses are large spherical viruses coated with spikes of proteins that help the virus bind and infect healthy cells. When looked under a microscope, these spikes appear like a crown (Latin = corona), hence the name. Underneath the spikes, there is a membrane, and inside the membrane is contained the genetic material of the virus (RNA) (Tizaoui et al.).

The key players of the immune response

To understand the immune response to SARS-CoV-2, let’s first look at the key players of the immunity. The first line of defense against infection is constituted by the innate immune system on the mucosa’s linings (for example, nose and throat). These cells get rapidly activated after an infection. In turn, they activate the second line of defense, called the acquired immunity. Acquired immunity comprises B-cells, in charge of the antibody response, and T-cells, in charge of killing the infected cells. 

Immune response to SARS-CoV-2

SARS-CoV-2 gains entry into the human body by binding to a receptor known as angiotensin-converting enzyme 2 (ACE2). ACE2 is found on the surface of cells that line the lungs, heart, blood vessels, intestinal tract, and kidneys (Tizaoui et al.).

 

Once the virus has entered the organism, the immune response to SARS-CoV-2 involves two parallel mechanisms: cell-mediated immunity and antibody production (Chowdhury et al.).

 

Cell-mediated immune response

Once the cells of the innate immune response have engaged the acquired immunity, T-cells become activated. There are two types of T-cells, both critical in the cell-mediated immune response. Those called CD4+ T cells are responsible for killing virus-infected cells, while those called CD8+ T cells help B-cells in the production of antibodies. If there is a high viral load in the lungs, many cells would be infected, meaning that many cells would need to be destroyed by CD4+ T cells, causing severe damages to the tissues (Oliveira et al.). 

 

Antibody production

Once activated by the CD8+ T cells, B cells are able to mount an antibody response against the virus, which leads to the production of neutralizing antibodies, an essential tool to fight the infection.

 

The severity of the disease

During the course of the pandemic, we’ve seen that the severity of the disease varies greatly in patients. This broad spectrum is likely due to differences in the viral load (how much virus is present in the tissues) but also to differences in the immune response mounted against the virus.

 

The reason behind the differences in the immune response is still not fully understood. It could be linked to diverse degrees of B-cells and T-cells activation (Jeyanathan et al.); however, further studies in the near future will better elucidate the mechanism.

 

As we age, our immune system becomes a bit less “reactive,” and this explains why severe COVID-19 diseases are often seen in the elderly (Chen et al.). However, an exacerbation of the immune reaction causing life-threatening symptoms can also occur in young patients, meaning that the severity is not necessarily proportional to the infected individual’s age.

 

The role of inflammation

As we’ve seen, in some patients, there is an overactivation of the immune response. This causes an excessive release of pro-inflammatory molecules called cytokines, resulting in very high levels of inflammation. Inflammation drives tissue damage, primarily in the lungs but also in other sites of the infection (Tay et al.).

 

For these reasons, anti-inflammatory drugs already approved for other immune-related inflammatory diseases such as rheumatoid arthritis and lupus have been approved for emergency use in COVID-19 disease.

 

Virus plasticity

A virus’ plasticity is its ability to mutate. It is not uncommon to see multiple variants of the same virus; that is why we have a different flu vaccine every year. SARS-CoV-2, as many other viruses, is able to mutate (Tizaoui et al.). Some mutant variants of a virus might be benign or even weakened. However, some others can be concerning because more “efficient” than the original one. For example, the SARS-CoV-2 variant identified in the UK in November 2020 is better at evading immune surveillance. While this is not necessarily linked to an increased severity or mortality, mutant strains like this one can be more transmissible. Additionally, the UK variant seems also better at creating a stronger bond with the infected cells.

Vaccines and novel therapeutic strategies for COVID-19

In 2020, great scientific efforts worldwide had been put into developing vaccines and drugs to treat severely ill patients. In these two avenues lies the hope for the future. 

 

Vaccines

Several different vaccines have been developed; some are still being tested, while others are already being administered in many countries. Although they are being produced by different Biotech/Pharma industries, they all rely on a similar approach: using a viral fragment to trigger antibodies’ production. Thanks to these antibodies, the immune system cells will have the tools to fight the infection in the future, making the person immune to the disease (Chung et al.). 

The vaccines’ main differences lie in the delivery system of the viral fragment, which can be encapsulated into lipid vesicles or put inside an inactivated virus that has been engineered to be harmless for humans. 

Antibody therapies

Another great promise for the future comes from the development of neutralizing antibodies to treat and prevent COVID-19. These are obtained and purified from COVID-19 patients, and they can be used to treat individuals at higher risk of developing severe disease (Garcia-Beltran et al.). At the moment, there are more than 100 clinical trials ongoing worldwide to investigate the efficacy and safety of this promising therapeutic approach, and the results are eagerly awaited. 

 

COVID-19 pandemic - what’s on the horizon

At this point, it is still hard to predict when the pandemic will finish. Vaccines are going to play a significant role in this. For sure, we still have a few months ahead that will see lockdowns and tailored restrictions. Forecasts from epidemiologists vary and depend on several factors. These include how and when people will develop immunity to the virus, whether seasonality affects its spread, and also, very importantly, the choices made by governments or individuals. 

 

To end the pandemic, the virus must be eliminated worldwide, which most scientists agree is nearly impossible given its widespread, or people must build sufficient immunity through infection or vaccine. The estimate for the threshold of immune people to stop the spread varies. However, it seems that between 60 to 80% of the population must be resistant to the infection for the virus to stop spreading. This is called herd immunity.  Herd immunity happens when a virus can’t spread anymore because it keeps encountering people that are protected against the infection, either because they already had it or – better- because they have been vaccinated. Thanks to the wide-scale and speedy vaccination campaigns going on all over the world, in 2021, many countries will hopefully reach herd immunity during the fall and we will eventually see the light at the end of the tunnel.

References 

 

  1. Chen, Yiyin et al. "Aging in Covid-19: Vulnerability, Immunity and Intervention." Ageing research reviews, vol. 65, 2021, pp. 101205-101205, PubMed, doi:10.1016/j.arr.2020.101205.

  2. Chowdhury, Mohammad Asaduzzaman et al. "Immune Response in Covid-19: A Review." Journal of Infection and Public Health, vol. 13, no. 11, 2020, pp. 1619-1629, doi:https://doi.org/10.1016/j.jiph.2020.07.001.

  3. Chung, Jee Young et al. "Covid-19 Vaccines: The Status and Perspectives in Delivery Points of View." Advanced drug delivery reviews, vol. 170, 2020, pp. 1-25, PubMed, doi:10.1016/j.addr.2020.12.011.

  4. Garcia-Beltran, Wilfredo F. et al. "Covid-19-Neutralizing Antibodies Predict Disease Severity and Survival." Cell, vol. 184, no. 2, 2021, pp. 476-488.e411, PubMed, doi:10.1016/j.cell.2020.12.015.

  5. Jeyanathan, Mangalakumari et al. "Immunological Considerations for Covid-19 Vaccine Strategies." Nature reviews. Immunology, vol. 20, no. 10, 2020, pp. 615-632, PubMed, doi:10.1038/s41577-020-00434-6.

  6. Machhi, Jatin et al. "The Natural History, Pathobiology, and Clinical Manifestations of Sars-Cov-2 Infections." Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, vol. 15, no. 3, 2020, pp. 359-386, PubMed, doi:10.1007/s11481-020-09944-5.

  7. Oliveira, Daniela S. et al. "Immune Response in Covid-19: What Do We Currently Know?" Microbial pathogenesis, vol. 148, 2020, pp. 104484-104484, PubMed, doi:10.1016/j.micpath.2020.104484.

  8. Tay, Matthew Zirui et al. "The Trinity of Covid-19: Immunity, Inflammation and Intervention." Nature reviews. Immunology, vol. 20, no. 6, 2020, pp. 363-374, PubMed, doi:10.1038/s41577-020-0311-8.

  9. Tizaoui, Kalthoum et al. "Update of the Current Knowledge on Genetics, Evolution, Immunopathogenesis, and Transmission for Coronavirus Disease 19 (Covid-19)." International journal of biological sciences, vol. 16, no. 15, 2020, pp. 2906-2923, PubMed, doi:10.7150/ijbs.48812.