Johns Hopkins Researchers Identify Immune System Pathway That May Stop COVID-19 Infection

SARS-COV-2 Virus Particles on Cell

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

Blocking Immune System Pathway May Stop COVID-19 Infection, Prevent Severe Organ Damage

While the world waits eagerly for 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 also are focusing on better understanding how SARS-CoV-2 attacks the body in the search for other means of stopping its devastating impact. The key to one possibility — blocking a protein that enables the virus to turn the immune system against healthy cells — has been identified in a recent study by a team of Johns Hopkins Medicine researchers.

Based on their findings, the researchers believe that inhibiting the protein, known as factor D, also will curtail the potentially deadly inflammatory reactions that many patients have to the virus.

Making the discovery even more exciting is that there may already be drugs in development and testing for other diseases that can do the required blocking.

The study was published recently in the journal Blood.

Scientists already know that spike proteins on the surface of the SARS-CoV-2 virus — making the pathogen look like the spiny ball from a medieval mace — are the means by which it attaches to cells targeted for infection. To do this, the 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 making up most organs. Facilitated by its initial binding with heparan sulfate, SARS-CoV-2 then uses another cell-surface component, the protein known as angiotensin-converting enzyme 2 (ACE2), as its doorway into the attacked cell.

The Johns Hopkins Medicine team discovered that when SARS-CoV-2 ties up heparan sulfate, it prevents factor H from using the sugar molecule to bind with cells. Factor H’s normal function is to regulate 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 destroyed by the defense mechanism nature intended to safeguard them.

“Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions — what we call the alternative pathway of complement, or APC — that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs,” says study senior author Robert Brodsky, M.D., director of the hematology division at the Johns Hopkins University School of Medicine. “The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage happens.”

The APC is one of three chain reaction processes involving the splitting and combining of more than 20 different proteins — known as complement proteins — that usually gets activated when bacteria or viruses invade the body. The end product of this complement cascade, a structure called membrane attack complex (MAC), forms on the surface of the invader and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope. However, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, that regulate the APC, keep it in check 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 subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the 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 — setting off the APC cascade and blocking factor H from connecting with the sugar — and in turn, disabling the complement regulation by which factor H deters a misdirected immune response.

In turn, the researchers say, the resulting immune system response to chemicals released by the lysing of killed cells could be responsible for the organ damage and failures seen in severe cases of COVID-19.

Most notably, Brodsky says, the research team found by blocking another complement protein, known as factor D, which works immediately upstream in the pathway from factor H, 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, the APC wasn’t activated by the virus spike proteins,” Brodsky says. “We believe that when the SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in the complement-mediated killing of normal cells because factor H, a key regulator of the APC, can’t do its job.”

To better understand what happens, Brodsky says think of the APC like a car in motion.

“If the brakes are disabled, the gas pedal can be floored without restraint, very likely leading to a crash and destruction,” he explains. “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.”

Brodsky adds that cell death and organ damage from a misdirected APC associated with factor H suppression is already known to occur in several complement-related human diseases, including age-related macular degeneration, a leading cause of vision loss for people age 50 and older; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes clots to block blood flow to the kidneys.

Brodsky and his colleagues hope that their work will encourage more study into the potential use against COVID-19 of complement-inhibiting drugs already in the pipeline for other diseases.

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

Reference: “Direct activation of the alternative complement pathway by 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 team are lead author Jia Yu; Xuan Yuan; Hang Chen; Shruti Chaturvedi, M.B.B.S.; and Evan Braunstein, M.D., 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 one, especially those related to clinical therapies and drug regimens, are still early in concept and small in sample size. This will require rigorous research, testing and peer review, all of which take time, before solid conclusions for clinical care and disease prevention can be made.

16 Comments on "Johns Hopkins Researchers Identify Immune System Pathway That May Stop COVID-19 Infection"

  1. REBEL’S DAILY REPORTS

    The brain is a biological computer that can manufacture all of us and every living thing on Earth. Each species has a unique brain that takes the food the we give ourselves and makes us whatever we may be biologically programed to be. If the human body needs 9 different amino acids to create all the different kinds of cells that the body needs to make us then why not give the body the 9 different amino acids in every day meals to ourselves and see what happens because then that biological computer in our minds can then maybe have the cure for fighting the coronavirus and all it needed was the combination of all those 9 amino acids in our food daily to make the cells to overtake the damage that the coronavirus can cause. There is a recipe for a food dish called Adelynn’s Miracle Beans recipe that has all the 9 different amino acids as well as many other nutrients the body needs. Perhaps if we were to give those that are sick from coronavirus 2 servings of this Adelynn’s Miracle Beans recipe daily 5-6 hours apart and also give 2 Centrum equivalent vitamins with a bean meal 5-6 hours apart. This will give one’s body all the proteins, vitamins and minerals that a human body needs to create any kind of blood cell. Maybe the human body will figure out a way to kill the coronavirus as well as other flues and colds if we give it the ingredients for it to do so! Someone try it. It beats dying or suffering from the illness. I know that taking 2 Centrum equivalent in one day with a meal 5 hours apart does help one get rid of the flu and colds because I have been doing it for 25 years and it always help me stop getting sicker every time I felt like I was getting the flu. So maybe eating Adelynn’s Miracle Beans and taking the vitamins will help make people with the coronavirus get better. Read facebook.com/ron.mccune.3 for much more info.

  2. No more colds by William wells

    Treatment for covid

  3. This sounds really goo and give hope. How widely available will it be also. The big question cost? Most insurance companies will not pay for experimental cures.

  4. Shamima Mondal | October 18, 2020 at 4:49 am | Reply

    Great news & Article about kill Coronavirus to eat daily increase Immune system food . Protein , Vitamin & Mineral – sounds great . I do take 500mg Vitamin C . Thank you So much .

  5. I did mentioned 10 year’s ago that ! human Brain is a most powerful Computer . And Brain function is combined with many Cell . 🙋
    —– Brain has memory Cell & When ! We do forget something ! Brain memory Cell try to practice – back & forth & remember that – like Computer past history . 🙋
    —– That’s ! Why Brain flued needs proper nutrition food to keep Immune system healthy
    —- I do hope ! Scientist will find ! Someday to invest healthy Brain . And ! it can even cure Alzheimer’s too .
    — Thank you . 🙋

  6. stephen schaffer | October 18, 2020 at 8:14 am | Reply

    what a great electron microscope picture as the lead into the article.
    next time, how about doing a bit of work and identifying the cell?

  7. I note it’s a sugar that the spike hooks upon. People eat too much sugar nowadays, processed food is packed with sugar, we are literally being poisoned by these processed food manufacturers. Un top of that many of the pre-existing conditions that make people especially vulnerable to the virus are diabetes and obesity. Once again sugar is the poison. stop eating processed food, Raw and cooked veggies in every meal, the least processed the better. Sure if you want a sweet treat from time to time, ok indulge yourself, but don’t eat daily in every meal processed food with extra sugar added.

  8. with all do respect. after that bullshit stunt they did for trump, I am skeptical of anything they say now. that hospital really put their representation on the line for what, TRUMP

  9. Lifelong Dem walked far away | October 18, 2020 at 2:01 pm | Reply

    With all do(it’s due) respect Johns Hopkins invented modern healthcare. I know that is not included in gender studies.

  10. I know how to stop the virus you need plasma from a NULL BLOOD TYPE because it won’t be able to imprint to mutate… I have this blood

  11. Is this medication along the same lines as Humira and other type of biologics used for RA,etc..?

  12. Samatha N Duncan | October 19, 2020 at 1:25 am | Reply

    Kristi Hill, Wtf? How do you confuse JOHN HOPKINS and WALTER REED? No disrespect intended but a fair amount of criticism is justified for publicly sharing your careless misinformed opinion without the slightest attempt at double checking your info.

  13. Charles Haerle | October 19, 2020 at 4:50 am | Reply

    Please don’t confuse science with politics. One shoukd have very little to do with the other.

  14. My immunology is a bit rusty, but if these cells are infected, the normal result by the immune system would be to kill the cell anyway, but through programmed cell death (“apoptosis”).

    I suspect the problem that wasn’t clarified in the article is lysis by the complement system is messy and dumps a lot stuff from the dying cell into its environment which are bad for healthy cells, such as digestive enzymes.

  15. @rassalas it’s a sugar in the biochemical sense, not the nutritional sense. Without these polysaccharides (complex structural chains of sugars) on the surface of our cells, our cells couldn’t function and we would literally fall apart, since they’re involved in cell to cell adhesion. That said, we do eat too much sugar, but reducing sugar intake wouldn’t have an effect on these surface polysaccharides, as our cells would synthesize them from other carbon sources.

  16. Seltum Pinheiro | October 20, 2020 at 2:37 am | Reply

    If hot water can’t cure a disease which is a result of cold fusion process like say covid 19 which mimics snake venom of king cobra and the lower versions like viper and krait probably done using coal distillation process on a mass scale then it has to be a continuous process of electronics which no tablet or vaccine can cure. Using satellites all they do is lower the continuity to zero and u all thing the disease has been cured. U can select and attack and kill people with diseases whom you don’t want to survive. Charles Darwin theory in the dustbin.

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