By Randolph Fillmore
COVID-19 research increasingly reveals how the disease interferes with the body’s immune system, and why older people are more vulnerable to its long-term effects. Researchers are also investigating whether COVID-19 permanently impairs the immune system.
A study by Johns Hopkins Medicine researchers published in the September 2, 2020 issue of the journal Blood has begun lighting up the internet and creating plenty of buzz. Now, everyone is asking - “What is factor D and how may knowledge about it help stop COVID-19?”
The study, titled “Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition,” focused on gaining a better understanding of how SARS-CoV-2 attacks the body, causing COVID-19, and ways to stop those attacks.
Thanks to their study, the researchers have some clues. One game changing possibility is that by blocking a protein in the immune system that enables the virus to turn a victim’s immune system against itself and start damaging healthy cells, the damaging effects can be subverted.
The Johns Hopkins team concluded that inhibiting the action of a protein, called “factor D,” may stop deadly inflammatory reactions many patients have after acquiring the virus. More good news is that there may already be drugs in development and testing that can block factor D.
What is factor D?
None of this is simple as it involves unraveling some of the deeper aspects of the immune system. “Hang on, Ernie. It’s going to be a bump-y ride!”
Scientists already know that the spike-like proteins on the surface of the SARS-CoV-2 virus -- making the pathogen look like a golf ball with thorns – allows the molecule to attach to cells targeted for infection. The spikes first grab hold of a substance called “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. After 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 a “doorway” to get into the cell.
The Johns Hopkins Medicine team found that when SARS-CoV-2 ties up heparan sulfate, it prevents another substance – factor H – from using the sugar molecule to bind with cells. The normal function of factor H 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 immune system – the very defense mechanism nature intended to safeguard them.
In other words, with factor H functionally dismantled by factor D, the immune system goes crazy and attacks healthy cells. This is also what autoimmune diseases do.
"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 of healthy organs if misdirected by the immune system," explained 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."
According to Dr. Brodsky, 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 by disrupting a virus' outer envelope. However, explained the researchers, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a variety of complement proteins, including factor H, that regulate the APC, keep it in check and protect normal cells from being damaged by MACs.
Is that clear? (Yes, it’s complicated. But stay tuned.)
The researchers next used normal human blood serum and three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the APC, then goes on to “hijack” the immune system and endanger normal cells. They found that two of the immune system subunits, called S1 and S2, are the components that bind the virus to heparan sulfate. This binding sets off the APC cascade and blocks factor H from connecting with the sugar, thereby disabling the complement regulation by which factor H keeps the immune response under control.
The immune system’s response to chemicals released by killed cells could be responsible for the serious organ damage and organ failures seen in severe cases of COVID-19.
(This is no simple influenza virus!)
The researchers hypothesized that by blocking another complement protein, called “factor D,” which works immediately upstream in the pathway from factor H, they could stop the destructive chain of events triggered by SARS-CoV-2. In other words, they used factor D to stop the virus from messing with factor H. It worked.
"When we added a small molecule that inhibits the function of factor D, the APC wasn't activated by the virus spike proteins," explained Dr. Brodsky. "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."
Dr. Brodsky compared this activity to a car in motion…but in trouble.
"If the brakes are disabled, the gas pedal can be floored without restraint, very likely leading to a crash and destruction," he explained. "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 re-applied and the immune system reset."
Dr. Brodsky added 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. That includes age-related macular degeneration, a leading cause of vision loss for people age 50 and over and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes blood clots to block blood flow to the kidneys.
Drugs that work like their experiments are already “in the pipeline,” said Dr. Brodsky. That means they are under development and/or in clinical trials.
"There are a number of these drugs that will be FDA-approved and in clinical practice within the next two years," said Brodsky "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 other factor D – “The Dive” or, what does it all mean? My take…
What the Johns Hopkins research shows is that COVID-19 induces the immune system into acting against itself, not unlike autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis, multiple sclerosis or, lupus. None of them are known to be caused by a virus, however, and the exact cause of autoimmune disorders is unknown, although some hypothesize that some microorganisms, bacteria or viruses, may trigger changes that “confuse” the immune system and lead to an autoimmune disorder.
According to “Dr. Wikipedia,” factor D is a “serine protease that stimulates glucose transport for triglyceride accumulation in fats cells and inhibits lipolysis” (did you get that?) (https://en.wikipedia.org/wiki/Factor_D). The Johns Hopkins research shows that factor D just may be the key to stopping COVID-19’s most dangerous, devastating and clandestine function – breaking into cells and hijacking the immune system, enlisting it its most dastardly work -murder.
Colonel Mustard, in the library, with the wrench.
It may be important to note that Dr. Wikipedia adds that “the level of Factor D is decreased in the obese, this reduction may be due to high activity or to resistance, but exact cause is not totally known.” Obesity has become one of the better-known risk factors for serious COVID-19 involvement, just ask the former New Jersey governor, Chris Christie. Also, clues that those with already compromised immune systems are especially vulnerable to COVID-19 has been in the spotlight from the beginning.
Dr. Wikipedia goes on to say that “factor D is synthesized by the liver and adipocytes (fat cells) with the latter being the major source.” In other words, COVID-19 likes and feeds on fat cells. Factor D has no known natural inhibitors in the body. Most of factor D is eliminated through the kidneys. However, “…in patients with renal disease, factor D was found at elevated levels. The alternative pathway is capable of operating even at low levels of factor D, and deficiencies in levels of factor D are rare.”
This means people with kidney disease are quite vulnerable to having their conditions worsen if they contract the virus.
What the “autonimmune-ness” of COVID-19 may also mean is that the “long haul” effects, as they have been called, that is the long-term symptoms and health difficulties associated with having had COVID-19, may not be unlike the long-haul aspects of autoimmune diseases. The question here is whether the immune system is permanently impaired, even in those who are first off asymptomatic? And does this mean that with an impaired immune system, we can expect little to no immunity to the virus? This hint has already been dropped when researchers wonder about people who re-contract COVID-19 after having had it before. They just don’t generate enough antibodies, suggesting that their immune systems have been compromised. (More on this farther along, with comments by the expert, Dr. Brodsky)
That older people are particularly vulnerable to COVID-19 makes sense here because the immune system grows weaker with age. Also, that men seem to be more likely than women to die from COVID-19 is a departure from some known aspects of other autoimmune diseases, such as lupus and MS, which are known to strike women more often than men. Some explanations for why women are more prone to autoimmune diseases can be explained by their generally stronger immune systems. Mothers impart part of their immune system to their babies who then, over time build their own immune systems. It may be that stronger immune systems can more easily go haywire, somehow; the weaker the immune system, if one is “immunocompromised,” infections can set in more easily.
(For more on this possibility, check out “An Elegant Defense” a book on the immune system that has been both cheered and criticized. See in more resources.)
A final note: TV addicts may be tired of seeing commercials for the array of new drugs that fight the symptoms of autoimmune diseases. Many of these drugs have very pretty commercial names, like “Skyrizi” (risankizumab-rzaa). The scientific names of these drugs all end in “mab,” standing for “monoclonal antibody.” Monoclonal antibodies are man-made proteins that act like human antibodies in the immune system and are made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Warnings come with these medications, alerting users to very dangerous, potential side effects, such as developing tuberculosis (TB).
A monoclonal antibody drug with the pharmaceutical name “ravulizumab,” and the commercial name of ULTOMIRIS®, is now aimed at COVID-19, as discussed below.
What has been made clearer by this new research is that COVID-19 is truly a monster. It creates its own, temporary, unique autoimmune disease. It is no simple influenza virus wannabe. Those who acquire it can be asymptomatic carriers, or they can be dead, or somewhere in between. That makes COVID-19 an insidious, evil, opportunistic disease that is to be feared. And don’t let anyone - anyone - tell you differently.
The hope is that strong and promising research, like that described above, just may be able to stop COVID-19 in its nasty tracks.
A Q&A with Dr. Brodsky
Q - By activating the immune system to essentially attack itself, does that mean that COVID-19 creates its own autoimmune disease? Isn’t that far, far different from “normal” influenza virus activity?
A - Yes, in a sense the virus does set off a transient autoimmune or autoinflammatory disease. Once the spike proteins decrease (as the virus clears) complement is no longer unregulated and the process resolves.
Q - Does the hijacking of the immune system this way also relate to what has become called the difficulties of the so-called “long haulers” who – like people with autoimmune diseases – have a lifetime of difficulty?
A - Hard to know. We still don’t understand how many people have late effects from COVID-19
Q - Is the drug you are referring to from Alexion Pharmaceuticals, Inc. who are conducting a global Phase 3 study to investigate ULTOMIRIS®(ravulizumab-cwvz)?
A – Yes, Alexion is sponsoring a trial with ravulizumab for COVID-19 patients. Ravulizumab blocks complement downstream of Factor H. In vitro it can block the complement attack triggered by the spike proteins and may be a promising drug therapy. There are several small case series of eculizumab (another C5 inhibitor) being beneficial to patients with COVID-19. However, our data suggest that blocking upstream of factor H, such as with a factor D inhibitor, or a C3 inhibitor, may be an even more effective strategy.
Q - Does this pathway involvement mean that a “simple” vaccine that confers immunity, like a flu vaccine, is not going to be very effective, especially if the immune system is compromised through the “cascade of events”?
A - No. A vaccine will likely be effective if it can prevent the viral load from increasing to the point where complement gets activated. If there are fewer viral particles around, there will be fewer spike proteins to bind heparan sulfate and, hence, less activation of the alternative pathway of complement.
Q - “Doctor Wikipedia” says that “This protein (factor D) is also a serine protease that is secreted by adipocytes into the bloodstream. Finally, the encoded protein has a high level of expression in fat, suggesting a role for adipose tissue in immune system biology…” does that connect to the fact that the obese seem to be at greater risk for poor outcomes of death?
A - Very interesting hypothesis. I can’t say for sure but there is no question that obese people have more inflammation, due in part, to complement activation than non-obese patients. How much this is due to factor D levels is unclear. It is also true that heparan sulfate levels on endothelial cells seems to decrease with age and seems to be decreased in pts with the metabolic syndrome; hence, it theoretically would be easier to occupy a great percentage of the heparan sulfate binding sites with less virus in these individuals.
Dr. Brodsky's major clinical research involves the study of aplastic anemia, paroxysmal nocturnal hemoglobinuria and other bone marrow failure disorders. Dr. Brodsky and his colleagues in neurology and rheumatology study severe autoimmune disorders including, scleroderma, myasthenia gravis, multiple sclerosis and autoimmune hematologic disorders.
Johns Hopkins Medicine:
Dr. Brodsky bio and research information:
Clinical trial looks at reducing immune response to help those with serious COVID-19 symptoms:
An Elegant Defense: The Extraordinary New Science of the Immune System: A Tale in Four Lives, by Matt Richtel
NIH trial of monoclonal antibodies to fight COVID-19:
ULTOMIRIS® (ravulizumab-cwvz) now being tested for COVID-19:
Learn more about drugs made with monoclonal antibodies. SKYRIZI (risankizumab-rzaa) (* it is not for COVID-19, but the website is useful for learning about monoclonal antibodies):