Natural Killer Cells May Play a Role in Severe COVID-19: Study
Wed, April 21, 2021

Natural Killer Cells May Play a Role in Severe COVID-19: Study


A new study associated natural killer cells with severe COVID-19. The immune responses from these cells might be the reason why some develop severe symptoms.

The link between natural killer cells and severe COVID-19 was revealed by researchers at Karolinska Institute, a research medical university in Sweden. They found that early activation of the cells could be excessively strong. The activation was also observed different from moderate COVID-19. This might explain intense inflammation among certain patients. They published their findings in the journal Science Immunology.

US Surveillance of Severe COVID-19 Cases

When the human body encounters an infection, cells of innate immunity will immediately respond to contain the situation. Neutrophils and macrophages respond to the site of infection and kill the pathogens and infected cells. Inflammation is a common phenomenon during immune responses to allow immune cells quickly reach the site. The same phenomenon is used to promptly repair damaged tissues. But if inflammation goes out of control, it can lead to damage.

If innate immune cells fail, adaptive immunity is notified to send reinforcement. B and T cells respond after some time once the pathogens are identified. During the engagement, adaptive immunity releases antibodies to disable the invaders to make it easier for immune cells to eliminate them. But before that happens, the person may be experiencing moderate to severe symptoms. This increases the risk of health complications.

According to the US Centers for Disease Control and Prevention, a federal agency, the overall cumulative COVID-19 related hospitalization rate was 151.7 per 100,000 people. The rates were greater among adults aged 65 years and older at 412.9 per 100,000 persons. It was followed by adults aged 50 to 64 years at 228.1 per 100,000 persons, as of Week 33 ending on August 15, 2020. The hospitalization rate was defined as severe COVID-19.

By ethnicity, the hospitalization rate among non-Hispanic American Indians or Alaska Natives was around 4.9 times higher than non-Hispanic Whites. While the rate among non-Hispanic Blacks and Hispanics or Latinos was about 4.7 times greater than non-Hispanic Whites. In terms of mortality, the death rate based on death certificate data was 7.8% attributed to influenza, pneumonia, and COVID-19. It was lower than the 12.6% in week 32 but it could go higher after certificates were processed.

There are many possible causes of severe COVID-19. From pre-existing health conditions to overreacting immune systems. As such, hospitals are doing what they can to provide the best supportive care to address signs of complications, which can induce organ failure and untimely death.



Natural Killer Cells May Be Blamed for Severe COVID-19

At Karolinska Institute (KI), researchers investigated what else could be causing severe COVID-19. Their search led them to a type of immune cell: the natural killer (NK) cell. While NK cells could effectively turn the tides, their activation must be timely to prevent adverse outcomes. Overstimulated NK cells could become uncontrollable and override inhibitory signals, which would upset a crucial balance in an immune response.

"The type of NK cell activation detected differed considerably in patients with moderate compared to severe disease," said Niklas Björkström, the lead author of the study and immunology researcher at the Center for Infectious Medicine at KI.

In the study, researchers recruited 27 patients with COVID-19 after being admitted to KI Hospital. Out of 27 patients, 10 had moderate and 17 had severe COVID-19. A total of 17 healthy people negative of COVID-19 antibody activity were recruited as controls. All 44 participants were processed and analyzed in three consecutive weeks from April to May 2020. Their blood samples were obtained and analyzed for NK cell activity.

The flow cytometry panel provided insights into the cellular activity of those cells. Results showed that those with severe COVID-19 exhibited overly aggressive NK cells. The cells in their blood were activated early after infection. The activation was also greater than normal and stronger than controls and those with moderate COVID-19.



Those with moderate COVID-19 expressed the standard NK cell response shared with other cells during viral infections. However, those with severe COVID-19 had higher expression levels of perforin, NKG2C, and Ksp37 proteins. The expression levels of these proteins translated the presence of adaptive NK cells. Adaptive NK cells could effectively kill infected cells than other NK cell types. But their early presence in the blood might be a misdirection. This might explain severe symptoms rapidly developed by some patients.

According to the British Society for Immunology, a UK-based organization of immunologists, NK cells are related to B and T cells in terms of a common parent. NK cells specialize in destroying virally infected cells and tumor cells. Unlike other certain cancer-kill cells, NK cells do not require priming. They can catch malignant cells as they patrol the human body.

The key to regulating the activity of NK cells is by balancing receptor signals. Since it does not need priming, NK cells rely on activation and inhibition receptors on its surface. If a cell is infected or malignant, its molecules will trigger the activation receptor. If a cell is friendly and healthy, its molecules will trigger the inhibition receptor. This is crucial because NK cells can produce cytokines that summon dendritic cells, macrophages, and other immune cells. High levels of cytokine can lead to widespread inflammation. If the delicate balance is disrupted, NK cells can immediately attack in an overly active way.



Normal cells express sufficient MHC class I molecules to inhibit NK cells. Tumor cells tend to express downregulated MHC class I molecules that activate NK cells. While transformed or infected cells may express increased molecules recognized by the activation receptors.

"Taken together, our findings provide additional insights into immune reactions in early SARS-CoV-2 infection and ensuing COVID-19 disease," added Björkström.

Researchers are now looking into the extent of the NK cell-mediated immune response in critically-ill COVID-19 patients. They are gathering evidence how such an immune response may contribute to the severity of the disease. The same evidence may reveal as well as specific benefits, which may be leveraged in clinical settings.