Earlier this year, Coutard et al proposed that the SARS-CoV-2 spike glycoprotein (S) contains a furin cleavage complex (FCC) which was likely playing a role in the pathogenicity of this particular virus. Fast forward a few weeks, and some further connections can be made with relevance for how we might interpret risk and choose interventions…
Viral Hijacking of Furin Protease
The FCC is a simple, basic amino acid region (RXXR) on the CoV-2 spike protein where the body’s own abundant furin protease (from hereon called ‘furin’) can attach and slice it in two. This is a chief distinguishing feature separating it from the otherwise genetically homologous SARS CoV-1, and the cleavage is part of the virus’s strategy for entering a target cell. It’s considered the gain-of-function mutation that enabled CoV-2 to jump to humans** and rapidly spread to pandemic levels.
In addition to using furin to gain entry into the host cell, CoV-2 also utilizes endogenous furin to cleave the S protein in the trans-Golgi network right after virion assembly. This latter mechanism separates the furin mechanism from other virally-hijacked proteases (like TMRPCC2), potently increasing the pathogenicity of CoV-2 (Figure 1). Note that infection with a variant of SARS C0V-2 which omits the FCC site resulted in a blunted illness in hamsters.
Braun and Sauter note that the ability of viruses to exploit furin may have major effects on their pathogenicity. In fact, as observed in the hamster study mentioned above, the same virus without the FCC might be avirulent, whereas the addition of the FCC can allow the virus to spread systemically and cause high rates of mortality. Furin is present in most tissue and is highly expressed in lungs.
Figure 1. A schematic diagram of the process of SARS CoV and SARS CoV 2 infecting host cells. Note the distribution of furin (the red “packman” protein) acts at cell surface and intracellularly on viral replication. [There is both membrane bound and cytosolic furin- KF]
As we’ve previously blogged about, furin plays a role in the potent virulence of dengue fever and other aggressive infections, including various avian influenzas. Today, as I was chatting with a friend of mine about furin, I did further research and noted that anthrax toxin is liberated by furin from Bacillus anthracis.
Of particular note was the fact that furin cleavage allows the anthrax toxin to flood the body BEFORE innate immunity kicks in effectively, significantly increasing lethality.
The same is noted in SARS CoV-2, where viral load can overwhelm the system before innate immunity can kick in and control it. I’ve wondered whether this delay had more to do with underlying comorbidities inhibiting a directed, antiviral innate immune response because of pre-existing baseline inflammation- and I still believe this is important.
But interestingly, could furin itself influence both the virus-initiated delayed immune response AND the problematic comorbidity response? The answer is yes.
Furin is a key protease in humans. It is ubiquitous in nature, including in mammals, where it is found in the Golgi apparatus and on the cell surface of most tissue cell types. Furin exists in both membrane-bound and secreted forms. Furin cleaves and activates a diverse group of about 100 proproteins and peptides in normal human physiology. Higher plasma furin levels have been identified in individuals on the cardiometabolic continuum- years before the onset of diabetes. Furin, independent of all other risk factors, is associated with increased risk of diabetes, hypertriglyceridemia, hyperinsulinemia, hypertension, obesity and all-cause mortality. ***
As Fernandez et al. explain, “Regarding potential mechanisms, as furin is responsible for the maturation of the insulin pro‐receptor, one could speculate that more furin in the circulation reflects a compensatory mechanism to increase the synthesis of active insulin receptors. Another possible mechanism of action of furin in DM development may be via pancreatic β‐cells as furin has been demonstrated to control the proliferation and differentiation of pancreatic β‐cell lines and to be involved in the maturation of insulin secretory granules.”
Perhaps individuals with the comorbidities associated with COVID-19 may have higher baseline furin that increases SARS-CoV-2 infectivity and pathogenicity?
Given how ubiquitous furin proteases are in normal human physiology, I’ll corral together some of its roles that coincide with known COVID-19 pathogenic mechanisms. Could all of these be increased when baseline furin is increased?
- Furin is the suspected cause of CoV-2’s aggressive infectivity and pathogenicity, including delayed innate immune response (see figure 1).
- Furin is directly involved in modulating the renin angiotensin aldosterone system, including activating the pro-renin receptor, which mediates formation of vasoconstrictor angiotensin. Recall angiotensin promotes release of aldosterone, sparing sodium at the expense of potassium. Hypokalemia is a common finding in COVID-19.
- Coagulopathy involving VWF and VIII appear to play a big role in many COVID-19 patients. Furin plays a role in activating clotting factor VIII
- Notably, furin expression is potently induced by hypoxia, as all three FUR promoters harbor binding sites for the hypoxia‐inducible factor‐1 (HIF‐1). Severe hypoxia is, of course, a hallmark finding in the most severe COVID-19 patients. (Berberine is a HIF-1 inhibitor with quite a few studies demonstrating this mechanism.)
Why has the US been hit so hard?
Regardless of whether furin elevation is a significant mechanistic link between cardiometabolic disease and COVID-19, as I suspect it could be, we know that those on the CM continuum are hardest hit, and more than 1-in-3 Americans have cardiometabolic disease and are therefore vulnerable to developing a more severe COVID-19.
Treatment: A few ideas
- We address underlying risk factors for COVID with our most potent interventions: diet and lifestyle. In this case, resolving cardiometabolic diseases will reduce furin and baseline inflammation, allowing the innate immune system to take charge and dispel of the virus.
- There are not a lot of pharma furin inhibitors. Is this because non-specific furin inhibition would have a severe side-effect profile given the myriad roles it plays? I suspect so…
- That said, it turns out heparin is a furin inhibitor and, given the coagulopathy seen in COVID-19, it’s in wide use in hospitalized patients and is associated with decreased mortality. Evidence for furin inhibition as an effective treatment?
The natural world has more options, which we can use in our plans now by choosing those we are familiar with and have a good safety profile. Of course, true benefit for these compounds hasn’t yet been established in clinical trials, and molecular docking studies can be thought of as pre-in vitro, a very preliminary first step.
We blogged about natural furin inhibitors early on in COVID-19. Four flavonoids can inhibit furin catalytic activity in vitro: Luteolin (demonstrated >95% inhibition in vitro), baicalein, chrysin and oroxylin. This preprint paper is a molecular docking study looking specifically at furin inhibition in CoV-2. EGCG, glutathione, Andrographis represent familiar products ID’d as effective and have known benefit via other SARS-CoV-2 mechanisms.
**I am not taking a position on whether this SARS CoV-2 was anything but a leap from bats to man (the answer doesn’t influence my need to develop best practice ideas based on understanding the pathophysiology) but if you are interested in an exhaustive and very well-referenced discussion on other possibilities (and also includes a brilliant education in all things furin), check out this Medium blog.
***I am not aware of a clinical laboratory offering serum furin. I believe it is limited to the research setting only. Perhaps that will change with COVID-19.
Thank you Dr Kara for a detailed view of furin, gain-of-function and how that explains the way co-morbidities make Americans so susceptible. I appreciate you noting how the virus enters the cell rapidly (infectious), but also impacts replication in the golgi apparatus increasing virulence as well. Many symptoms seem to involve epithelial tissues (except perhaps the role of RBCs in hypoxia and some neurological issues). Since the American Pattern Diet creates permeability in the gut, blood brain barrier, skin and other epithelial barriers, little wonder that metabolic syndrome (obesity, diabetes, etc) makes one susceptible.
Thanks, Scott. I agree. It will be interesting to see whether the furin cleavage complex is determined to be a central player in COVID pathogenesis. I think it will be. DrKF
You continue to be such a reliable and inspiring source of information for me. Like many CAM doctors I suppose, I am in private practice and have not had the benefit of default collaboration or corporate led best practices during this pandemic. However, your blog posts have been a guiding light, from the relevance of CAM doctors to evidenced based practice, during this time. Thank you so much for So generously sharing your knowledge. It’s inspiring and relevant.
Thank you, Dr. Fabbi. We appreciate your kind words SO much. DrKF
I was looking to see what the dosages were for luteolin, and I don’t see any. Do you know? And thanks for another terrific article. You have become one of my main go-to clinicians in all this. So much appreciation for your thoughtful analysis.
Thank you so much! We appreciate you following along with us. There are not any established dose recommendations for luteolin, particularly for COVID. Studies range widely and likely depend on various factors like age, need, health-status etc… that certainly might be why you’re having trouble landing on a dosage recommendation.