This post was reviewed by Dr. Brett Finlay from UBC- one of our subject matter experts.
Image credit: “Defense Protection Threat Free Photo” by Bru-nO is in the public domain.
The paper that we’ll be demystifying can be found here, if you want to follow along.
Our immune system is what keeps us safe from the bacterial and viral forces that conspire against us. Our skin and respiratory tract form barriers where the viral world meets our internal microcosm. White blood cells patrol our bloodstream, destroying invaders. Memory B cells and T cells in specific recognize past pathogens and give us a lasting immunity.
Certain viruses, like SARS-CoV-2, can turn these immune responses against us. Inflammation, the swollen redness created by the immune system to fight disease and remove damaged cells, plays a big role in the symptoms of COVID-19. In general, when inflammation goes haywire, it can cause tissue and organ damage. In the case of COVID-19, this can take the form of inflammation in the lungs.
Blood tests from severe COVID-19 patients have found high levels of inflammatory cytokines, small proteins used as signals by immune system to cause responses like inflammation. SARS, caused by SARS-CoV, has a similar effect, altering cytokine levels and other immune responses to cause certain symptoms. As such, cytokines are implicated in a well-known hypothesis for COVID-19 inflammation: the cytokine storm. As the name suggests, a cytokine storm is the release of an excess of cytokines, which causes large and possibly fatal amounts of inflammation. In fact, cytokine storms were a major cause of death by Spanish flu exactly 100 years ago, and by swine flu more recently.
Understanding a phenomenon so historically tied to viral infection mortality has drawn a huge amount of interest. Therefore, studying it in the context of SARS-CoV-2 propelled the team’s work into Cell, one of the preeminent scientific journals.
The problem with treating inflammation is that inflammatory response is turbulent, fluctuating every day from its many components working differently. A team from the National University of Singapore worked to characterize how these different components behave during a COVID-19 infection.
The team specifically looked at inflammatory changes during the early phases of infection to help guide future treatments. Along with 10 healthy volunteers, they looked at samples from 3 COVID-19 patients from Wuhan, China. To track the immune response, researchers used RT-PCR to measure transcription of genes associated with inflammation and immune function. For more on RT-PCR, check out this previous article.
Of the three patients, two had fairly mild cases. Both were in their mid-30s and had normal chest CT scans, and one even lacked a fever. The one patient with a severe case was 66 years old, required additional oxygen, and had worsening lesions in both of his lungs, according to the CT scan. As indicated by his heart rate and blood oxygen, his lowest point was at Day 5, after which his condition began to improve.
Researchers found that his blood had relatively high levels of gene expression for inflammation, cytokine signaling, and Toll-like receptors (TLRs), membrane proteins that immune cells use to recognize microbes. Oddly, this effect peaked at Day 6, the day after his lowest point. In fact, certain cytokines were within normal range until after the lowest point, such as the inflammatory IL-6 and TNF-α, the viral suppressant IFNA1/13, and the immune cell regulator, IL-2. Only levels of the inflammatory cytokine IL-1 and its corresponding receptor rose before the lowest point. As such, IL-1 could be the inflammatory driver of COVID-19, opening a potential avenue of treatment.
The severe patient also had lower expression of genes that activate T cells and MHC Class II, a molecule that presents viral peptides for the immune system to recognize. Likewise, expression of genes for the T cell itself were decreased. These elements of the immune system are key parts of the adaptive immune system, named so because it remembers previous viruses and adapts accordingly. It’s the mechanism that allows vaccines to program our immune system against specific diseases. By dampening the adaptive immune response, not only can SARS-CoV-2 do more damage to a patient, it can also linger around longer, potentially spreading the infection even more.
The mild patients had similar levels of gene expression to the healthy volunteers. Additionally, the team didn’t find a significant impact on adaptive or inflammatory markers after the patients were treated with lopinavir and ritonavir, two antiviral drugs generally used in COVID-19 treatment.
The relationship between the adaptive and inflammatory changes is still unclear. It could be that the low amount of T cells caused more inflammation. However, the inflammation may have instead caused T cells and away from the where the blood was sampled, into the lymph nodes and zones of infection. As such, there’s lots of room for further study. It’s also important to note that the small sample size of 3 patients, with only 1 severe patient, might not paint an accurate picture of the COVID-19 immune response in all patients. Based on this, a future study with a larger sample size is required.
The team at the National University of Singapore has made a lot of steps in figuring out how COVID-19 hijacks the immune system, and their work has laid down valuable foundation for future treatments.
Because when the immune system is in trouble, scientists have our back too.
