Cytokine Storms: COVID-19 Through an Immunology Lens

Written by: Justin Nguyen

Edited by: Sami Morse, Kathleen Navas, & Maura McDonaugh

It has been around a year since SARS-CoV-2, the novel virus that causes COVID-19, has taken the world by force, and researchers around the globe have worked tirelessly to bring the coronavirus to its heels through proactive public health measures. As case numbers across the United States plateau, thanks in-part to the vaccines on the market, you may be wondering, “Why on Earth was this virus so effective? Why were infectious diseases like Ebola more lethal, yet the coronavirus takes the crown for total number of deaths?” This can, in part, be explained by how our immune system responds against this specific virus.

A Recap of the Immune System

To better understand how SARS-CoV-2 interacts with our immune system, let us review some concepts. Our immune system fights against infectious diseases through two pathways: the innate immune response and the adaptive immune response.

For a general overview of our immune response, take a look at our blog on the immune system. During the innate stage, our immune cells find and destroy invading bugs (pathogens) by sensing general proteins that are commonly found on the surface of foreign cells, known as pathogen-associated molecular patterns (PAMPS). Once initiated, the innate immune response causes inflammation, helps to kill and neutralize the invading cells, and most importantly, turns on the next phase: the adaptive response. During this next stage, highly specific B cells are activated, which in turn, produce antibodies to help neutralize and destroy pathogens. Simultaneously, cytotoxic T cells are deployed to directly kill infected cells, and helper T cells are turned on to further specify B cell response, as well as augment the overall adaptive immune response. This well-coordinated mechanism is highly effective and results in cellular memory for the pathogen of interest, which makes it easier to clear upon subsequent re-infection.

The cells involved in the immune response vary widely in function, but for the purpose of understanding the mechanism by which coronavirus infection causes severe inflammation, we will focus on the cells that secrete a class of molecules called cytokines, the main culprit behind this phenomenon. Cytokines are “immune hormones” that facilitate both innate and adaptive responses, and cause a variety of responses depending on the type of cytokine and the target cell.

Cytokine Storms and COVID-19

Macrophages and neutrophils, two of the most important pro-inflammatory cells involved in the innate response, secrete cytokines, amplifying inflammation so that more immune cells are called in to help combat the virus. Additionally, recruited helper T cells can also secrete cytokines to help regulate both the innate and adaptive responses. While pathogens routinely trigger an immune response that involves cytokines, the severe symptoms that can come with COVID-19 infection are because of a cytokine overreaction--a storm.

One of the main causes here is a specific inflammatory cytokine: interleukin-6 (IL-6). This molecule is secreted by macrophages, T cells, and endothelial cells alike. In the case of SARS-CoV-2 infection, it is released after our immune cells recognize the coronavirus binding to and multiplying within alveolar epithelial cells (cells located on the lining of sacs used to transfer oxygen into the blood in your lungs). With some COVID-19 patients, IL-6 is secreted in an adequate amount, resulting in acute inflammation, jump-starting T and B cell activation, and subsequently helping clear the virus. But, for some people, namely individuals who are immunocompromised or have comorbidities, their immune response cells secrete IL-6 in excessive amounts due to a whole host of factors. These can include genetic differences in the patient, leading to a varied immune response or a failure to resolve the infection within a given time, allowing the virus to multiply in large amounts.

IL-6 causes inflammation, which in moderation, helps propel the immune response. However, if overproduced, the very same cytokine used to help fight infection can change from beneficial to harmful. Since SARS-CoV-2 attacks the alveolar cells, IL-6 will recruit more inflammatory cells to the lungs, which may ultimately destroy the lining of our lung cells and can cause progressively severe symptoms such as coughing, fatigue, dyspnea (shortness of breath), and acute respiratory distress syndrome (ARDS), which often leads to hospitalization.

What are the treatments for cytokine storms?

While the current array of vaccines being offered are excellent at preventing infection and possibly transmission of coronavirus, reducing the chance for ongoing infections to trigger cytokine storms requires therapeutic treatments. The most popular and effective treatments being used currently are corticosteroids and glucocorticoids. These drugs mimic the behavior of the hormone cortisol, which is involved in suppressing inflammatory responses such as cytokine storms in the body. They have shown promise in reducing 28-day mortality rates in patients that require ventilation or are experiencing severe symptoms.

But isn’t it a 1-2% mortality rate? Why should I be worried?

It’s true that several diseases, such as Ebola, are notably more virulent (severe in symptoms) with an average 50% mortality rate, but when talking about transmissibility (the ability to infect others), SARS-CoV-2 poses a very real threat. It is not lethal enough to halt transmission, can transmit from asymptomatic carriers, and relies on easily transmissible respiratory droplets rather than mucosal fluids and blood, as with Ebola. This explains how as of early March 2021, 2.5 million people have died in just over a year as compared to 11,325 deaths from the 2014-2016 Ebola outbreak. Additionally, you may want to consider the long-term effects of the coronavirus that have been documented: symptoms such as shortness of breath, fatigue, loss of smell, and perhaps more chronic disorders that may arise for many months after infection.

In conclusion

The SARS-CoV-2 virus triggers our immune system to release inflammatory mediators in order to clear infection. However, if uncontrolled, this very same inflammation may cause severe symptoms with long-lasting impact, and, in some cases, death. Although some treatments show promise in preventing severe outcomes, vaccine distribution and herd immunity are the best way to ensure safety from the SARS-CoV-2 virus.

Results from ongoing research and the current understanding of COVID-19 are constantly evolving. This post contains information that was last updated on April 6, 2021.

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