New research suggests that the severity of COVID-19 is linked to the complement system, one of the oldest parts of the innate immune system and also coagulation dysfunction.
Researchers at Columbia University Irving Medical Center found people with age-related macular degeneration were more likely to develop severe complications from COVID-19 and were more likely to die from the disease. The complement system is overactive in patients with age-related macular degeneration. The researchers also found that coagulation dysfunction was also linked to the severity of COVID-19 symptoms and mutations in certain coagulation and complement genes were associated with the hospitalization of COVID-19 patients.
“Together, these results provide important insights into the pathophysiology of COVID-19 and paint a picture for the role of complement and coagulation pathways in determining clinical outcomes of patients infected with SARS-CoV-2,” said Sagi Shapira, PhD, MPH, who co-led the study.
The researchers investigated the role of coagulation and complement after conducting a survey of viral mimicry in more than 7,000 viruses. Viruses have proteins that mimic proteins in host cells, which are used to trick those host cells into helping the virus with part of its lifecycle. The researchers thought that if they were able to identify the mimics, it would help them determine how viruses cause disease. The researchers found that coronaviruses were particularly good at mimicking host proteins, especially those involved in coagulation and the proteins of the complement system.
“We mapped over 140 cellular proteins that are structurally mimicked by coronaviruses (CoVs) and identified complement and coagulation pathways as targets of this strategy across all CoV strains,” said Shapira.
The proteins in the complement system eliminate pathogens such as viruses by sticking to them, and by doing so, mark the pathogens for destruction. The proteins can also increase coagulation and inflammation, which can cause problems if not kept in check. “The new coronavirus—by mimicking complement or coagulation proteins—might drive both systems into a hyperactive state,” suggests Shapira.
The researchers then investigated whether patients with hyperactive complement or coagulation disorders were more susceptible to the virus. The researchers looked at patients with age-related macular degeneration and disorders linked to coagulation such as thrombosis.
Out of 11,000 patients at Columbia University Irving Medical Center who were suspected as having contracted COVID-19, 25% of the patients with age-related macular degeneration died from COVID-19 compared to the standard mortality rate of 8.5%. Around 20% of those patients required intubation. The researchers said the increase in mortality and intubation rates could not be explained by the sex or age of the patients.
Obese patients and individuals with diabetes are known to be at a high risk of developing severe COVID-19 symptoms and the complement system is more active in obese patients and those with diabetes, which could indicate why there is a greater mortality rate in those patients.
The researchers found the SARS-CoV-2 virus causes a robust activation of both the complement and coagulation systems. “We found that complement is one of the most differentially expressed pathways in SARS-CoV-2-infected patients,” said Nicholas Tatonetti, PhD, co-lead of the study. “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.”
Potentially, drugs used to suppress the complement system could be useful in treating patients with severe COVID-19 systems, as could drugs that are used to treat coagulation disorders. Clinical trials are already underway to test the effectiveness of those drugs on patients with severe symptoms of COVID-19.
You can read more about the study in the paper – Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection – which was recently published in Nature Medicine. DOI: 10.1038/s41591-020-1021-2