Out-of-control immune systems and COVID-19: How a single protein might be the answer

TORONTO — While scientists race to develop a safe and effective vaccine to prevent the spread of COVID-19, researchers at Johns Hopkins University have focused on preventing severe organ damage from patients’ own immune systems by inhibiting an important protein.

The team from the university’s school of medicine sought to better understand how SARS-CoV-2, the virus that causes COVID-19, attacks the body and causes severe inflammatory responses in certain individuals.

The study’s senior author, Dr. Robert Brodsky, director of the hematology division at the 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 complement system.

“This is really our first defence against a lot of bacteria and viruses,” he told CTVNews.ca during a telephone interview from Baltimore, Md. on Thursday.

The complement system enhances, or complements, the ability of antibodies and phagocytic cells to clear pathogens from the body. This system consists of more than 30 proteins, including two – factor H and factor D – that were of particular interest to the research team.

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

“It’s what allows the complement system to fight off foreign organisms, but not destroy host tissues,” Brodsky explained.

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

During an infection of SARS-CoV-2, the famous spike proteins on the surface of the virus, which make it resemble a medieval mace, allow it to attach to healthy cells in the human body. In order to do this, the spikes latch on to heparan sulfate – a large sugar molecule found on the surface of cells in the lungs, blood vessels, and smooth muscle of most organs.

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

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

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

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

BLOCKING THE IMMUNE RESPONSE

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

“Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defence mechanism nature intended to safeguard them,” the researchers said.

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

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

To simplify, Brodsky compared the complement system’s immune response to a car in motion.

“The viral spike proteins disable the biological brakes, factor H, enabling the gas pedal, factor D, to accelerate the immune system and cause cell, tissue and organ devastation. Inhibit factor D, and 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-inhibiting drug to block factor D and the chain of events leading to the immune system’s attack on the body’s healthy cells.

While the drug hasn’t been approved by the U.S. Food and Drug Association (FDA) yet, Brodsky said it’s being tested in late-stage 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 a use in the fight against COVID-19.

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

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

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