Purdue researchers working with an international team of scientists have discovered that a hyperactive immune response in lung cells is likely behind some of the most severe COVID-19 cases.
The finding could have implicationsfor treating the most severe cases of the disease.
Using publicly available data, Purdue researchers unexpectedly found that immune response to COVID-19 was being triggered in the cells of the lungs through the immune complement system.
The complement system is a series of plasma proteins that activate immune response after encountering a pathogen. It is one of the oldest systems of immune defense, found even in sea sponges.
Some complement immune response is good, but hyperactivation is likely driving the inflammation and damage in some of the more severe and life threatening COVID cases.
Dr. Ben Afzali is Chief of the Immunoregulation Section of the National Institute of Health. He said in mammals the dominant source of the complement system is in the liver, which secretes its complement into the blood.
“Unexpectedly, we found the cells of the lungs produce complement in response to infection,” he said. “Not only did they switch on the genes for complement, but they also started activating the complement inside the cell.”
What’s unique, according to Afzali, is that complement activation was specific to the inflamed lungs and researchers found minimal complement system activation in the blood.
“Suggesting that the complement activation [in the lungs] is to an extent driving the disease,” he said. “Very recently a group published that activation of complement is an independent risk factor for death for COVID-19. So this is a very significant finding.”
Part of what makes the finding so significant is that many of the drugs being used as interventions for COVID-19 have targeted the blood.
“Of course it wasn’t working because all the activation, we think, is happening in the lungs,” Afzali said. “So in order to target it effectively, you probably need a drug that penetrates the cells and switches it off.”
The finding led researchers to look at what drugs could be used to reverse the effect and found that a combination of two drugs could reduce inflammation of lung cells back to baseline.
Dr. Majid Kazemian is a Purdue researcher and one of the lead authors on the study. He said his team looked at a series of FDA-approved drugs to see what kind of genes they switched off - cross-referencing that list with the genes that were turned on in COVID-19.
“Using this simple process, what came up is that Ruxolitinib, in combination with another antiviral drug, Remdesivir, could indeed turn off part of the activity of this complement which was turned on inside the cells.”
Dr. Ben Afzali said the drugs could be effective in reducing inflammation back to baseline.
“Whether that will work in a majority of patients or in a subset we’ll need to wait until the clinic trails. But it is quite encouraging I think.”
Afzali described the finding as “striking” but said he doesn’t want to give people false hope and cautioned that it will take clinical trials to confirm that the combination of drugs will work on patients.
The other question is how early patients can be given the treatment. Afzali said if scientists can find biomarkers that help predict who will have a more severe reaction to COVID-19 it could help them start treatment early.
“A lot of clinical trials have been disappointing because you’ve got the right drug, it’s just too late at that point by the time you start instigating it,” he said. “A lot of the drugs we have are going to be reasonably effective if we could only target the right people to give it to early enough.”