Blocking the pathway of the immune system can stop COVID-19 Infection, prevents serious organ damage
While the world eagerly awaits a safe and effective vaccine to prevent infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the COVID-19 pandemic, researchers are also focusing on better understanding how SARS-CoV-2 attacks the body in search of other ways to stop its devastating effects. The key to a possibility – blocking a protein that allows the virus to turn the immune system against healthy cells – has been identified in a recent study by a team of researchers at Johns Hopkins Medicine.
Based on their findings, the researchers believe that inhibition of the protein, known as factor D, will also limit the potentially fatal inflammatory reactions that many patients have to the virus.
To make the discovery even more exciting is that there may already be substances under development and testing for other diseases that can make the necessary blockage.
The study was recently published in the journal Blood.
Researchers already know that spike proteins on the surface of the SARS-CoV-2 virus – which makes the pathogen look like the spiny ball of a medieval lace – are the means by which it binds to cells targeted at infection. To do this, spikes first grab hold of heparan sulfate, a large, complex sugar molecule found on the surface of cells in the lungs, blood vessels, and smooth muscle that make up most organs. SARS-CoV-2 then facilitates its initial binding with heparan sulfate and then uses another cell surface component, the protein known as angiotensin-converting enzyme 2 (ACE2), as its doorway into the affected cell.
The Johns Hopkins Medicine team discovered that when SARS-CoV-2 binds heparan sulfate, it prevents factor H from using the sugar molecule to bind to cells. The normal function of factor H is to regulate the chemical signals that trigger inflammation and prevent the immune system from damaging healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defense mechanism designed to protect them.
Previous research has suggested that SARS-CoV-2, along with binding heparan sulfate, activates a cascading array of biological reactions – what we call the alternative complement pathways, or APCs – that can lead to inflammation and cell destruction if misdiagnosed by the immune system in healthy organs, ”says senior author Robert Brodsky, MD, director of the hematology department at Johns Hopkins University School of Medicine. “The goal of our study was to discover how the virus activates this pathway and find a way to inhibit it before the damage occurs.”
APC is one of three chain reaction processes that involve the division and combination of more than 20 different proteins – known as complement proteins – that are normally activated when bacteria or viruses invade the body. The end product of this complement cascade, a structure called the membrane attack complex (MAC), forms on the surface of the intruder and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope. However, MACs can also occur on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, which regulates APC, keeps it in check, and therefore protects normal cells from damaging MACs.
In a series of experiments, Brodsky and his colleagues typically used human blood serum and three subunits of the SARS-CoV-2 peak protein to discover exactly how the virus activates APC, hijacks the immune system, and endangers normal cells. They discovered that two of the subunits, called S1 and S2, are the components that bind the virus to heparan sulfate – which counteracts the APC cascade and blocks factor H from binding to sugar – and in turn disables complement regulation by which factor H deters a incorrectly controlled immune response.
In turn, the researchers say that the resulting immune system response to chemicals released by lysing killed cells may be responsible for organ damage and failure seen in severe cases of COVID-19.
Brodsky says that by blocking another complement protein, known as factor D, which acts immediately upstream of factor H, the research team found that they were able to stop the destructive chain of events triggered by SARS-CoV-2.
“When we added a small molecule that inhibits the function of factor D, APC was not activated by the virus tip proteins,” says Brodsky. “We believe that when SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in complement-mediated killing of normal cells because factor H, a key regulator of APC, cannot do its job.”
To better understand what’s going on, Brodsky says think of the APC as a moving car.
“If the brakes are deactivated, the accelerator pedal can be floored without restraint, which is likely to lead to a crash and damage,” he explains. The viral tip proteins inactivate the biological brakes, factor H, enabling the accelerator pedal, factor D, to accelerate the immune system and cause destruction of cells, tissues and organs. Inhibits factor D and the brakes can be reapplied and the immune system reset. ”
Brodsky adds that cell death and organ damage from a miscontrolled APC associated with factor H suppression are already known to occur in several complement-related human diseases, including age-related macular degeneration, a leading cause of vision loss in people aged 50 years and older; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes blood clots to block blood flow to the kidneys.
Brodsky and his colleagues hope their work will encourage more research into the potential use against COVID-19 of complement-inhibiting drugs already in use in other diseases.
“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 in conjunction with vaccines to help control the spread of COVID-19 and prevent future viral pandemics.”
Reference: “Direct activation of the alternative complement pathway with SARS-CoV-2 spike proteins is blocked by factor D inhibition” by Jia Yu, Xuan Yuan, Hang Chen, Shruti Chaturvedi, Evan M. Braunstein, and Robert A. Brodsky, 2 September 2020, Blood.
DOI: 10.1182 / blood.2020008248
Along with Brodsky, the other members of the Johns Hopkins Medicine research group are lead author Jia Yu; Xuan Yuan; Hang Chen; Shruti Chaturvedi, MBBS; and Evan Braunstein, MD, Ph.D.
The study was supported by National Heart, Lung and Blood Institute grant R01 HL133113.
Disclaimer: Johns Hopkins Medicine researchers are working tirelessly to find ways to better understand and eventually eliminate COVID-19 and the virus that causes it. Discoveries like this, especially those related to clinical therapies and drug regimens, are still early in concept and small in sample size. This will require thorough research, testing and peer review, all of which take time before solid conclusions can be drawn for clinical treatment and disease prevention.