Severe vs Mild COVID-19 infections: differences in immune responses

COVID-19 is a global crisis that has infected more than 21 million people worldwide. While most infected individuals only experience mild symptoms of the virus, 15% of all reported cases required hospitalization, 2% were admitted to an intensive care unit (ICU) and 5% resulted in death. Why is it that some people get really sick from COVID-19, and others don’t? The answer may lie in a weakened innate immune response — our body’s natural defense mechanism against viruses and pathogens.

A group of scientists from Stanford University and University of Hong Kong led a study analyzing the blood samples from 76 COVID-19 patients and 69 healthy individuals. They treated the blood samples with viral particles and found that the white blood cells of infected patients were less able to produce IL-6, a type of cytokine. Cytokines are small signaling proteins secreted by the immune system that call on an army of white blood cells to combat viruses and other foreign particles. This means that COVID-19 infected individuals were less able to respond to viruses —and thus have a crippled innate immunity— in their blood. The sicker the patient is from COVID-19, the more suppressed the immune response is.

However, IL-6 is a pro-inflammatory cytokine, meaning that when it signals for white blood cells to attack tissues infected with viruses, it drives inflammation to the site of infection and contributes to the severity of COVID-19 symptoms. Therefore, it seemed counterintuitive that in a severe COVID-19 case, the white blood cells would secrete less cytokines. Indeed, when the team analyzed levels of cytokines in the blood, they found that cytokines were increased in infected patients, even more so in severely infected individuals. If the innate immune system in an infected individual is weakened, where did all the cytokines come from? They must have originated somewhere else in the body.

Digging further for more clues, the researchers found increased amounts of bacterial DNA in the blood of infected patients. They also found higher levels of proteins that are indicators of lung inflammation. Therefore, they postulated that the virus, and possibly bacteria, in the lungs caused the lungs to secrete high levels of cytokines in the blood, driving lung inflammation and severity of the disease. Meanwhile, the innate immune system of infected patients are still suppressed in the blood, undermining their ability to fight off the virus.

There have been many studies showing the increase in cytokines in patients infected with COVID-19, but no one has properly understood why that is. This study shows, for the first time, that people with severe COVID-19 infections have a much weaker innate immunity in their blood, and thus the increase in cytokines most likely originated from the lungs, not from their blood. This new understanding of the mechanism of COVID-19 infection would hopefully allow us to better develop therapeutics to target severe COVID-19 infection in the future.

The three co-authors of this paper are Prabhu S. Arunachala and Florian Wimmers, both postdoctoral scholars in Stanford University School of Medicine, and Chris Mok Ka Pun, a research assistant professor in Hong Kong University School of Public Health.

Managing Correspondent: Wei Li

Press Article: Study reveals immune-system deviations in severe COVID-19 cases. Stanford Medicine News Center.

Original Scientific Article: Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science.

Image Credit: Gerd Altmann from Pixabay