Blocking immune system pathways may stop Coronavirus disease Infection to prevent serious organ damage
Although the world is eagerly waiting for a safe and effective vaccine to prevent the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this is the virus behind the COVID-19 pandemic. Researchers are also working to better understand how SARS-CoV-2 attacks the human body in order to find other ways to stop its destructive effects. In a recent study, a team of Johns Hopkins Medicine researchers identified the key to a possibility-blocking a protein that allows the virus to target the immune system against healthy cells.
Based on their findings, the researchers believe that inhibiting this protein called factor D will also reduce the potentially fatal inflammatory response of many patients to the virus.
What makes the discovery even more exciting is that other disease drugs that can block the desired block may already be developed and tested.
The research was recently published in the journal blood.
Scientists already know that the spike protein on the surface of the SARS-CoV-2 virus (which makes the pathogen look like a spike in a medieval mace) is a means of attaching it to infected cells. To do this, we must first seize heparan sulfate, which is a large complex sugar molecule found on the surface of lungs, blood vessels and smooth muscle cells in most organs. Due to the initial binding to heparan sulfate, SARS-CoV-2 subsequently used another cell surface component, a protein called angiotensin-converting enzyme 2 (ACE2), as a channel into the attacked cell.
The Johns Hopkins University Medical Team found that when SARS-CoV-2 binds to heparan sulfate, it prevents factor H from using sugar molecules to bind to cells. The normal function of factor H is to regulate the chemical signals that trigger inflammation and protect the immune system from damaging healthy cells. Without this protection, the cells in the lungs, heart, kidneys and other organs would be destroyed by defense mechanisms designed to protect them.
“Previous studies have shown that in combination with heparan sulfate, SARS-CoV-2 activates a series of cascades of biological responses-we call the alternative pathway of complement or APC-if misled by heparin, it can lead to inflammation and cell destruction. One, said Robert Brodsky, MD, director of the Department of Hematology at Johns Hopkins University School of Medicine. “The purpose of our research is to discover how the virus activates this pathway and find a way to inhibit it before damage occurs. method. “
APC is one of the three chain reaction processes involving the division and binding of more than 20 different proteins (called complement proteins), and is usually activated when bacteria or viruses invade the body. The final product of this complement cascade, a structure called the membrane attack complex (MAC), forms on the surface of the invader and causes damage by forming holes in the bacterial membrane or destroying the outer shell of the virus. However, MAC can also appear on the membranes of healthy cells. Fortunately, humans have many complement proteins, including factor H, which can regulate APC and keep it under control, thereby protecting normal cells from MACs.
In a series of experiments, Brodsky and his colleagues used normal human serum and the three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates APC, hijacks the immune system and endangers normal cells. . They discovered two subunits, called S1 and S2, which are the components that bind the virus to heparan sulfate-blocking the APC cascade and preventing factor H from linking to sugar-so that complement cannot be regulated by this factor H prevents a misleading immune response.
The researchers say that, in turn, the immune system response to chemicals released by the lysis of killed cells may be the cause of the organ damage and failure seen in severe COVID-19 cases.
Brodsky said, most notably, the research team found that by blocking another complement protein called factor D, this protein can act directly upstream of the factor H pathway, thereby preventing SARS-CoV-2 triggering Chain of destructive events.
“When we add small molecules that inhibit the function of factor D, APC will not be activated by the viral spike protein,” Brodsky said. “We believe that when the SARS-CoV-2 spike protein binds to heparan sulfate, it will trigger an increase in complement-mediated killing of normal cells because the key regulator of APC, H, cannot function.”
To better understand what happened, Brodsky said, APC is like a moving car.
He explained: “If the brakes are disabled, the accelerator pedal can be laid on the floor without restriction, which is likely to cause collision and damage.” The viral spike protein disables the biological braking of factor H and causes the accelerator pedal of factor D to accelerate Immune system and cause destruction of cells, tissues and organs. Suppress factor D, you can step on the brakes again and reset the immune system. “
Brodsky added that cell death and organ damage caused by misdirection of APC related to factor H inhibition has occurred in several complement-related human diseases, including age-related macular degeneration, which is the loss of vision in people 50 years and older. The main reason. Atypical hemolytic uremic syndrome (aHUS), a rare disease that causes blood clots to block blood flow to the kidneys.
Brodsky and his colleagues hope that their work will encourage more research to investigate the potential use of complement-suppressing drugs that are already targeting other diseases for COVID-19.
Brodsky said: “In the next two years, many of these drugs will be approved by the FDA and will be used in clinical practice.” “Maybe one or more of them can be used with vaccines to help control the spread of COVID-19. And avoid future viral pandemics.”
References: Jia Yu, Xuan Yuan, Hang Hang, Shruti Chaturvedi, Evan M. Braunstein, and Robert A. Brodsky, “The direct activation of SARS-CoV-2 synaptic protein alternative complement pathway is blocked by factor D inhibition”, September 2nd 2020 blood.
DOI: 10.1182 / blood.2020008248
Other members of the Johns Hopkins University Medical Research Group, along with Brodsky, are the first author Jia Yu. Xuan Yuan Hang Chen Shruti Chaturvedi, MBBS; and Evan Braunstein, MD
The research was funded by the National Heart, Lung, and Blood Institute, R01 HL133113.
Disclaimer: Researchers at Johns Hopkins University School of Medicine have worked tirelessly to find ways to better understand and ultimately eliminate COVID-19 and its virus. Discoveries like this, especially those related to clinical therapies and drug treatments, are conceptually very early and the sample size is small. This will require rigorous research, testing, and peer review, all of which will take time to draw reliable conclusions about clinical care and disease prevention.