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COVID Over-Reactions Linked to Ancient Part of Immune System

3D illustration of leukocytes attacking virus in bloodstream
Yurchanka Siarhei/Shutterstock

One of the oldest parts of our immune systems is called “complement,” and it has just been implicated in leading to more severe cases of COVID-19 in some patients. Scientists are hoping research that moderates its reaction can help fight the disease.

Billion-Year-Old Immunity

Complement is a part of the immune system that begins with a protein named C3. This protein has been found in sea sponges, leading researchers to conclude that the complement system is at least a billion years old. It gets its unusual name from the fact that it “complements” antibodies in fighting infections. 

When a foreign organism activates the system, a chain reaction is begun in which C3 is split, which leads another protein to be split, and so on down the line through 30 different proteins. As they are split, the proteins release cytokines, and the system fights infection through increasing coagulation and inflammation, bursting invading cells, and devouring cell debris.

While that might sound beneficial, if the system goes haywire, it can cause harm. 

A Great Mimic

By looking at the more than 7,000 viruses that exist on Earth, Researchers at Columbia University’s Vagelos College of Physicians and Surgeons found that coronaviruses are particularly good mimics—especially when it comes to impersonating the proteins involved in the complement system and coagulation. They theorize that this mimicry might drive these systems into overdrive, leading to problematic outcomes in patients who are prone to hyperactive coagulation or complement disorders. 

So the researchers looked at patients who contracted COVID-19 who also had macular degeneration, a condition caused by an overactive complement system. Sure enough, they found that of the 11,000 patients treated for the virus at Columbia University Irving Medical Center, those having age-related macular degeneration died at a rate of over 25% versus the average death rate of 8.5%. The difference remained even after accounting for patient age and sex.

“Complement is also more active in obesity and diabetes,” Shapira says, “and may help explain, at least in part, why people with those conditions also have a greater mortality risk from COVID.” The study also showed that individuals with coagulation disorders such as hemophilia were also more likely to die from SARS-CoV-2, the disease caused by COVID-19. 

Further research showed a genetic marker that started a robust complement system reaction in COVID-infected patients.

“We found that complement is one of the most differentially expressed pathways in SARS-CoV-2 infected patients,” said Columbia’s Nicholas Tatonetti, who led the study with colleague Sagi Shapira. “As part of the immune system, you would expect to see complement activated, but it seems over and above what you’d see in other infections like the flu.”

Studies and Trials

Some medications can modulate the complement system, and the researchers hope that their work can point to further solutions to fight the virus. At least one study and one clinical trial is already underway.

“I think our findings provide a stronger foundation for the idea that coagulation and complement play a role in COVID, and will hopefully inspire others to evaluate this hypothesis and see if it’s something that can be useful for fighting the ongoing pandemic,” said Tatonetti.

The research has been published in the journal Nature Medicine.