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Johns Hopkins Researchers Recognize Immune System Pathway That Can Stop COVID-19 Infection

Cells of SARS-COV-2 Virus Particles

Colored scanning of the electron micrograph of a cell (purple) severely contaminated with SARS-CoV-2 virus particles (yellow). A recent study by Johns Hopkins Medicine shows that blocking a specific protein in a biological pathway can prevent SARS-CoV-2 infection and keep the virus from the wrong direction of the immune system. in healthy cells and organs. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Immune System Pathune Blocking May Be Stopped COVID-19 Infections, Prevent Severe Organ Damage

As the world eagerly waits for a safe and effective vaccine to prevent infections from severe acute respiratory respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the COVID-19 pandemic, researchers also focused on better understanding how SARS-CoV-2 attacks the body in search of other ways to stop the devastating effect its. The key to a possibility – blocking a protein that allows the virus to open the immune system against healthy cells – was identified in a recent study by a team of Johns Hopkins Medicine researchers.

Based on their findings, the researchers believe that protein suppression, known as factor D, will also alleviate the potentially fatal inflammatory reactions that many patients have with the virus.

Making the discovery even more exciting is that there may be developmental drugs and tests for other diseases that can do the necessary blocking.

The study was recently published in the journal Blood.

Scientists already know that spike proteins on the surface of the SARS-CoV-2 virus – making the pathogen look like a spiny ball from a medieval mace – are the means by which it attaches itself to cells targeted for infection. To do this, the spikes first touch the heparan sulfate, a large and complex sugar molecule located on the surface of the lung cells, blood vessels and smooth muscle that makes up most of the organs. Simplified by its initial binding to heparan sulfate, SARS-CoV-2 uses another cell-surface component, the protein known as angiotensin-convertting enzyme 2 (ACE2), as well as its gateway to the attack and cell.

The Johns Hopkins Medicine team discovered that when SARS-CoV-2 binds to heparan sulfate, it prevents factor H from using the sugar molecule to bind to cells. The normal function of Factor H is to control the chemical signals that trigger inflammation and keep the immune system from harming healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be damaged by the immune mechanism that naturally protects them.

“Previous research has suggested that along with heparan sulfate binding, SARS-CoV-2 activates a series of biological reactions – the so-called alternative pathway of completion, or APC – that can lead to inflammation and cell damage. if the immune system misleads the healthy organs, “said study senior author Robert Brodsky, MD, director of the hematology division at the Johns Hopkins University School of Medicine. “The purpose of our study was to discover how the virus activates this pathway and to find a way to prevent it before the injury occurs.”

APC is one of three chain reaction processes involving the breakdown and synthesis of more than 20 different proteins – known as auxiliary proteins – that are commonly activated when bacteria or viruses invade the body. The final product of this complete cascade, a structure called the membrane attack complex (MAC), forms on the surface of the conqueror and causes its breakdown, either creating holes in the bacterial membranes or disrupting the outer envelope of a virus. However, MACs can also appear on the membranes of healthy cells. Unfortunately, humans have a number of complementary proteins, including factor H, that control APC, maintain it properly and therefore, protect normal cells from damage by MACs.

In a series of experiments, Brodsky and his colleagues used normal human blood serum and three SARS-CoV-2 spike protein subunits to discover exactly how the virus activates APC, hijacked the immune system and threatened normal cells. They found that two of the subunits, called S1 and S2, were the components that bind the virus to heparan sulfate – which removes the APC cascade and blocks factor H from connecting to sugar – and vice versa, auxiliary adjustment is disabled by which factor H prevents a wrong direction of immune response.

In this regard, the researchers said, the resulting immune system response to chemicals released by the lysing of killed cells may be responsible for organ damage and failure seen in the severe case of COVID-19.

Most notably, Brodsky, the research team found by blocking another complementary protein, known as factor D, that works immediately in the pathway from factor H, they stopped the destructive chain of events triggered by SARS-CoV-2.

“When we add a small molecule that inhibits factor D function, APC is not activated by virus spike proteins,” Brodsky said. “We believe that when SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in auxiliary killing of normal cells because factor H, a key APC regulator, cannot its work. “

To better understand what was going on, Brodsky said to think of the APC as a moving car.

“If the brakes are disabled, the gas pedal can floor without restraint, likely leading to a crash and destruction,” he explains. “Viral spike proteins disable biological brakes, factor H, which activates the gas pedal, factor D, to accelerate the immune system and cause cell, tissue and organ damage. Prevent factor D, and the brakes can be reused and the immune system can be reset. “

Brodsky added that cell death and organ damage from a misdiagnosed APC associated with factor H inhibition are known to occur in many complementary diseases, including age-related macular degeneration, a primary cause of vision loss for people aged 50 and over; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes clots to block blood flow to the kidneys.

Brodsky and his colleagues hope their work will encourage further studies on the potential use against COVID-19 of complementary preventative drugs already in the pipeline for other diseases.

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

Reference: “Direct activation of alternative pathway supplementation of 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, September 2, 2020, Blood.
DOI: 10.1182 / blood.2020008248

Along with Brodsky, other members of the Johns Hopkins Medicine research team were led by 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: Researchers at Johns Hopkins Medicine are working tirelessly to find ways to better understand and eventually eliminate COVID-19 and the virus that causes it. Findings like this one, especially those related to clinical therapies and medication regimens, are still early in concept and small in sample size. This will require rigorous research, evaluation and peer review, all of which take time, before solid conclusions can be drawn for clinical care and disease prevention.

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