Mechanism Behind Long COVID May Have Been Discovered

Long COVID can linger for months after infection. Image Credit: Dragana Gordic/Shutterstock.com

Researchers may have discovered an underlying mechanism resulting in long COVID, the lingering condition following COVID-19 that leaves some people with brain fog, respiratory problems, and more. The research, published in The Public Library of Science ONE (PLOS ONE), hints at the production of an auto-antibody weeks after infection that disrupts the regulation of the immune system, resulting in the overactivation of immune proteins and inflammation. 

If the researchers are able to verify their findings and establish a connection to long COVID, the antibody would be a promising target as a therapy. 

“Everything that we’ve found is consistent with this antibody as the instigator of long COVID, so it’s an exciting development that merits further study,” said lead researcher John Arthur, professor and chief of the Division of Nephrology in the University of Arkansas for Medical Sciences (UAMS) College of Medicine, in a statement

The antibody in question targets an enzyme utilized heavily during COVID-19 infection, called ACE2. This enzyme is extremely important for SARS-CoV-2 virus particles to enter host cells, as they gain entry through the ACE2 receptor on the cell surface.

In typical infections, ACE2 breaks down an immune protein, resulting in decreased activation of the immune system. This prevents the immune system from doing damage to cells while it fights off the infection – but when SARS-CoV-2 infects cells and binds to the receptor, it prevents ACE2 from reducing this immune activity. Scientists believe this is one method in which COVID-19 damages the body to such a high extent.  

However, in long COVID patients, the researchers hypothesized that the body creates auto-antibodies against ACE2 that linger, resulting in lower ACE2 activity and damage from an overactive immune system. 

To test this, the researchers obtained plasma or serum from 80 patients – 67 with a history of COVID-19 infection, and 13 without. Using PCR tests, they screened the samples for the presence of ACE2 auto-antibodies in quantities that surpassed a certain threshold. They discovered that none of the 13 COVID-19-free patients had ACE2 auto-antibodies, and just 1 out of 20 outpatients with a positive PCR COVID-19 test that had a sample taken at a hospital shortly after infection had them. In contrast, the vast majority of samples taken 2 weeks after infection – and also those that were acutely hospitalized for COVID-19 – contained ACE2 auto-antibodies.  

The plasma containing the auto-antibodies elicited lower activity of ACE2, despite having comparable ACE2 levels in solution, suggesting the antibodies were interfering with the activity of the enzyme. When the scientists added the plasma containing auto-antibodies to samples that did not, they saw a decrease in ACE2 activity.  

The results suggest two things: that ACE2 auto-antibodies likely form weeks after COVID-19 infection; and these auto-antibodies can directly inhibit ACE2 activity, possibly resulting in inflammation and symptoms seen in long COVID. 

Following the breakthrough, the team hopes to push forward their research and fully verify their results. If this mechanism is the underlying cause of long COVID, a treatment could well be developed.  

“If we show that the whole hypothesis is right, that this interference of ACE2 really does cause long COVID, then it opens up many potential treatments,” Arthur said.  

“If our next steps confirm that this antibody is the cause of long COVID symptoms, there are medications that should work to treat them. If we get to that phase of research, the next step would be to test these drugs and hopefully relieve people of the symptoms they’re having.” 

 
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