Cytokine Storms and Immune System Response to SARS-CoV-2

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As more and more people are diagnosed with COVID-19 each day, we see that this disease can vary in its severity. Some people are asymptomatic, some have mild cases, and some have much more severe cases that are likely to produce lasting damage. The most severe of these COVID-19 cases are caused largely because the immune system, a system set in place to heal our bodies, ends up doing more harm than good. When people are infected by SARS-CoV-2, the virus that causes COVID-19, the virus can sometimes incite a dysfunctional and damaging immune system response.

Generally, once in the cell viruses will hijack the host cell to express viral DNA, create an optimized environment, and activate viral replication. The infected cell will detect virus replication through pattern recognition receptors. These receptors recognize the unusual RNA structures formed by the replicating virus and will activate two types of transcription factors. This activation will trigger the generation of cytokines. Cytokines are small signaling proteins that alter the immune system response. There are a variety of different types of cytokines, each with different functions – some are pro-inflammatory, some are anti-inflammatory. In this case, pro-inflammatory cytokines are produced in order to direct white blood cells to the infection site and increase inflammation.

Image: Pattern Recognition Receptor, Immune System Response

Inflammation can occur any time cells are damaged by bacteria, viruses, heat, toxins, or injury. Damaged cells release chemicals that will lead to swelling and will attract white blood cells to destroy the injured cells. This response can sometimes injure local tissue, but typically repair processes begin shortly after the inflammation and the tissue is restored.

A healthy immune response is capable of clearing away infected cells and inactivating the virus. Inflammation will occur, interferons will hinder virus replication, neutralizing antibodies will inactivate the virus, and white blood cells will eliminate infected cells and destroy the neutralized virus.

Like other respiratory diseases and coronaviruses, SARS-CoV-2 can interfere with this response and lead to an unhealthy and dysfunctional immune system response. Instead of cytokines helping the body, the overproduction of cytokines creates a cytokine storm that is harmful and damaging. A cytokine storm leads to hyperinflammation, which means that there is so much inflammation that the alveoli, or tiny air sacs in the lungs are damaged.

The damage to the alveoli can lead to pneumonia, where the alveoli in the lungs fill with fluid and breathing becomes extremely difficult. More severe cases can become Acute Respiratory Distress Syndrome (ARDS). At this stage, the fluid in the lungs and subsequent low blood oxygen levels stops other organs from receiving the oxygen they need to function. Ventilation is usually necessary for people with ARDS. Eventually, ARDS can progress into sepsis, where the inflammation spreads throughout the body and results in organ failure.

Image: Dysfunctional Immune Response, Healthy Immune Response

Survivors of ARDS and sepsis will usually have permanent damage and scarring. This damage occurs because the body replaces injured epithelial tissue (tissue that lines organs and blood vessels) with connective tissue. While connective tissue is necessary for the body – blood, bones, and cartilage are all composed of this tissue – too much of it in the wrong place can be harmful. In the lungs, connective tissue will replace the epithelial tissue on the damaged alveoli walls, thickening and hardening the lungs. Thicker walls mean it is more difficult for oxygen to diffuse out of the alveoli and into the bloodstream to reach other organs. This makes it harder to breathe and harder for other organs to function normally. Connective tissue can also replace damage on these other organs, making it more difficult for them to do their jobs. Since there is no way to remove this connective tissue, the damage is permanent.One factor that could affect why this cytokine storm can be so severe and can lead to so much damage is that the interferon response is sometimes diminished in SARS-CoV-2 infected cells. This means that virus replication is not well blocked by the body’s immune system. More virus replication could lead to a stronger, more overpowering cytokine response.

The cytokine storm lends clues as to why certain populations are more likely to be severely affected by COVID-19. Older people and people with compromised immune systems may be more likely to have a dysfunctional immune response, possibly because a restricted immune system has trouble fighting off infection early and allows infection to spread more rapidly. The healthier, more robust immune systems of younger people may potentially help them fight off the infection better. Another theory is that children’s immune systems are less developed, so their immune system is not aggressive enough to create a cytokine storm. However, more research still needs to be conducted to see the exact factors that lead to a damaging immune system response.

References:

Jennifer Tisoncik. “Into the Eye of the Cytokine Storm.” Microbiology and Molecular Biology Reviews 76(1): 16–32 (Mar 2012).

Mathew Tay. “The trinity of COVID-19: immunity, inflammation and intervention.” Nature Reviews Immunology (Apr 2020).

Mohsen Rokni. “Immune responses and pathogenesis of SARS‐CoV‐2 during an outbreak in Iran: Comparison with SARS and MERS.” Reviews in Medical Virology 30(3) (Apr 2020).

Qiang Liu. “The cytokine storm of severe influenza and development of immunomodulatory therapy.” Cellular & Molecular Immunology 13: 3–10 (2016).

Won-Young Kim. “Sepsis and Acute Respiratory Distress Syndrome: Recent Update.” Tuberculosis and Respiratory Diseases (Seoul) 79(2): 53–57 (Apr 2016).

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