Factor D: Is blocking this protein the key to preventing COVID-19 from damaging organs?

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TORONTO – As scientists rush to develop a safe and effective vaccine to prevent the spread of COVID-19, researchers at Johns Hopkins University have focused on preventing serious organ damage caused by patients’ immune systems by inhibiting an important protein. The team at the university’s medical school sought to gain a better understanding of how SARS-CoV-2, the virus that causes COVID-19, attacks the body and causes severe inflammatory reactions in some individuals.

Lead author of the study, Dr Robert Brodsky, director of the division of hematology at Johns Hopkins University School of Medicine, explained that their research focused on an integral part of the immune system called the innate immune system or the innate immune system. of the complement.

“It really is our first defense against a lot of bacteria and viruses,” he told CTVNews.ca in a telephone interview from Baltimore, Maryland on Thursday.

The complement system enhances or supplements the ability of antibodies and phagocytic cells to clear pathogens from the body. This system is made up of more than 30 proteins, two of which – factor H and factor D – which were of particular interest to the research team.

Factor H is a controlling protein that regulates chemical signals that trigger inflammation and the immune system.

“This is what allows the complement system to fight foreign organisms, but not destroy host tissue,” Brodsky explained.

Factor D is another protein in the complement system that is immediately upstream of factor H in the chain of immune events triggered by the virus.

During an infection with SARS-CoV-2, the famous spike proteins on the surface of the virus, which make it look like a medieval lump, allow it to attach to healthy cells in the human body. It does this by attaching the tips to heparan sulfate – a large sugar molecule found on the surface of cells in the lungs, blood vessels, and smooth muscles of most organs.

“Just related to heparan sulfate, [the virus] probably couldn’t enter the cell and start replication. But without heparan sulfate, there wouldn’t be enough of it to reach the ACE-2 receptor, ”he said.

Much attention has been paid to the role of the ACE-2 receptor protein (angiotensin-2 converting enzyme) and its role as the coronavirus entry point to infect a range of human cells.

However, Brodsky said the ACE-2 receptor is not found on all tissues, which is why his team focused on how the coronavirus binds to the heparan sulfate molecule.

“Heparin sulfate is on pretty much every cell, pretty much every cell in the body,” he said.

BLOCK IMMUNE RESPONSE

Returning to factor H, the researchers found that when the SARS-CoV-2 virus binds to the heparan sulfate sugar molecule in the cell, it occupies the site where the factor H protein would normally attach to protect that cell. of the body’s immune response.

“Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the natural defense mechanism designed to protect them,” the researchers said.

To prevent the virus from occupying the factor H spot on cells and leaving vital organs vulnerable to the body’s immune response, academics attempted to prevent this sequence of events from occurring by inhibiting factor D.

As mentioned earlier, factor D is located directly upstream of factor H in the complement system. By blocking factor D function, the sequence of immune events triggered by the invading virus will also be stopped.

For simplicity, Brodsky compared the immune response of the complement system to a moving car.

“The viral spike proteins deactivate the biological brakes, factor H, allowing the accelerator, factor D, to speed up the immune system and wreak havoc on cells, tissues and organs. Inhibit factor D, the brakes can be reapplied and the immune system reset, ”he explained.

In the lab, the research team used a small molecule in a complement inhibitor drug to block factor D and the chain of events leading to the immune system attacking healthy cells in the body.

Although the drug has yet to be approved by the U.S. Food and Drug Association (FDA), Brodsky said it is being tested in advanced clinical trials. He said there are already a number of other complement-inhibiting drugs in the pipeline for other diseases, including age-related macular degeneration, which may have use in the fight against COVID- 19.

“There are a number of these drugs that will be approved by the FDA and in clinical practice within the next two years,” Brodsky said. “Perhaps one or more of these could be combined with vaccines to help control the spread of COVID-19 and prevent future viral pandemics.”

The researchers’ findings were recently published in the journal Blood.

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