Covid-19: The ACE2 of Spades

Angiotensin-converting enzyme 2 (ACE2), a protein on the surface of the cell membrane, is now at center-stage in this outbreak as the key receptor for the spike glycoprotein of SARS-CoV-2. ACE2 is part of renin–angiotensin–aldosterone system (RAAS) is an elegant cascade of protein linkages that orchestrate key processes in human physiology by affecting the diameter of blood vessels. Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 (Covid-19) interface with the RAAS through ACE2 which functions as a receptor for both SARS viruses.

SARS-CoV-2 appears not only to gain initial entry through ACE2, but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert its protective effects in organs. ACE2 does this by degrading angiotensin II, a hormone produced locally within the kidney that acts on the central nervous system to regulate renal sympathetic nerve activity, renal function, and, therefore, blood pressure. Angiotensin II also mediates tissue injury through other effects not linked to its prime role in vascular control. Thus, we can see that ACE2 is a critical control element for a hormone that exerts widespread effects within the body.

As a hormone, angiotensin II circulates widely and exerts its effects on the vasculature of many target tissues. So it should not be unexpected to find that ACE2, its regulator, is equally widely distributed. This allows for a more localized (tissue / organ specific) control over the regional vasculature. To find out just how widely distributed ACE2 was, I wrote a small bioinformatics script and pinged a few sites. The results were surprising. A smaller list might have been produced by querying where ACE2 wasn’t. The list is quite long; I made the table scrollable to save space.

TISSUE DISTRIBUTION OF ACE2
SYSTEM ORGAN/TISSUE
CARDIOVASCULAR SYSTEM ATRIUM
CARDIOVASCULAR SYSTEM CORONARY ARTERY
CARDIOVASCULAR SYSTEM PULMONARY ARTERY
CARDIOVASCULAR SYSTEM VENTRICLE
DIGESTIVE SYSTEM COLON
DIGESTIVE SYSTEM DUODENUM
DIGESTIVE SYSTEM GALL BLADDER
DIGESTIVE SYSTEM ILEUM
DIGESTIVE SYSTEM JEJUNUM
DIGESTIVE SYSTEM LIVER
DIGESTIVE SYSTEM OESOPHAGUS
DIGESTIVE SYSTEM PANCREAS
DIGESTIVE SYSTEM RECTUM
ENDOCRINE SYSTEM ADRENAL GLAND
ENDOCRINE SYSTEM PINEAL GLAND
ENDOCRINE SYSTEM PITUITARY GLAND
ENDOCRINE SYSTEM THYROID GLAND
FEMALE REPRODUCTIVE CERVIX
FEMALE REPRODUCTIVE FALLOPIAN TUBE
FEMALE REPRODUCTIVE MAMMARY GLAND
FEMALE REPRODUCTIVE OVARY
HEMATOLOGIC SYSTEM SPLEEN
IMMUNE SYSTEM MONOCYTE
IMMUNE SYSTEM TONSIL
INTEGUMENT SKIN
LIQUID COMPARTMENT URINE
MALE REPRODUCTIVE PROSTATE
MALE REPRODUCTIVE TESTIS
MALE REPRODUCTIVE VAS DEFERENS
MUSCULO-SKELETAL SYSTEM SKELETAL MUSCLE
NERVOUS SYSTEM AMYGDALA
NERVOUS SYSTEM CAUDATE NUCLEUS
NERVOUS SYSTEM CEREBELLUM
NERVOUS SYSTEM CEREBRUM
NERVOUS SYSTEM FRONTAL CORTEX
NERVOUS SYSTEM HIPPOCAMPUS
NERVOUS SYSTEM HYPOTHALAMUS
NERVOUS SYSTEM MEDULLA OBLONGATA
NERVOUS SYSTEM NUCLEUS ACCUMBENS
NERVOUS SYSTEM OCCIPITAL CORTEX
NERVOUS SYSTEM PARIETAL CORTEX
NERVOUS SYSTEM SPINAL CORD
NERVOUS SYSTEM SUBSTANTIA NIGRA
OBSTETRICAL PLACENTA
OBSTETRICAL UMBILICAL CORD
RESPIRATORY SYSTEM LUNG
RESPIRATORY SYSTEM TRACHEA
SECRETIONS SEMEN
SENSORY SYSTEM CHOROID PLEXUS
UBIQUITOUS FAT TISSUE
URINARY SYSTEM RENAL CORTEX
URINARY SYSTEM URETER
URINARY SYSTEM URINARY BLADDER

SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. It has been postulated, but unproven, that unabated Angiotensin II activity may be in part responsible for organ injury in Covid-19. Although with Covid-19 it appears that the major nexus of infection is via the lungs, I think it is clear to see that ACE2 is widely spread throughout the body. This distribution also offers potential explanations as to why Covid-19 often presents as a mystifying series of symptoms. Let’s take a look by system and organ:

Kidneys

ACE2 is heavily represented in the tissues of the urinary tract. In a preprint (non-peer reviewed) article, SARS-CoV-2 was found to induce acute renal failure (ARF) in COVID-19 patients by damaging the delicate tubules of the kidneys, where metabolic wastes are removed via filtration. The researchers found that the virus directly infected these tubules and induced acute tubular damage by inducing an inflow of inflammatory cells known as macrophages into the interstitial tissues around the tubules, and also enhances the deposition of pro-inflammatory mediators known as complement onto the tubules themselves. However, in a separate study with a larger population group, investigators concluded that acute kidney injury was uncommon in Covid-19 and that SARS-CoV-2 infection did not result in an appreciable increase in the rate of acute kidney injury, or even aggravate Covid-19 patients who had pre-existing chronic kidney disease. Finally a third study seemed to indicate that the markers of active kidney inflammation were not uncommon upon hospital admissions for Covid-19. On admission, 43.9% of patients had protein in their urine (proteinuria) and 26.7% had blood in their urine (hematuria). Others had elevated serum creatinine (14.1%), elevated blood urea nitrogen (13.1%) and compromised glomerular filtration (13.1%). In this study acute kidney injury occurred in 5.1% of the patients.

Adipose Tissue

ACE2 is richly deposited on the surfaces of the body’s fat cells. In a preprint article (not peer-reviewed) investigators searched a variety of network databases and pubic data, and found the level of ACE2 expression in fat (adipose) tissue was in fact higher than in lung tissue, indicating that adipose tissue might be vulnerable to SARS-CoV-2 as well. The levels of ACE2 expressed by fat cells (adipocytes) were actually similar between non-obese individuals and obese individuals. However, since obese people have more adipose tissue they consequently have an increase in the number of cells expressing ACE2. This has lead to some speculation that the higher mortality rate in obese patients, sufferers from diabetes, and/or metabolic syndrome may in fact be due to viral activity in fat tissue.

Brain

Most of us are now familiar with the observation that a possible early sign of Covid-19 infection is a loss of smell or taste (anosmia). This observation is not unique; it has been observed for a variety of viral infections, including the common cold. It’s thought to be the result of a temporary disruption in the ability of the smell receptors to recognize chemical patterns. This can also lead to dysosmia —when you go to smell something and it smells like something else, usually something unpleasant. Since we can clearly see from the table that ACE2 is elaborately represented in nerve tissue, it begs the question whether the loss of smell associated with Covid-19 is the result SARS-CoV-2 infection of the olfactory sensory neurons and a sign that brain infection is now a possibility. Thankfully, this appears to not be the case. Investigators have reported that in mouse and human datasets the olfactory sensory neurons do not express two key genes required for SARS-CoV-2 entry, ACE2 and TMPRSS2. In contrast, olfactory epithelial support cells and stem cells express both of these genes, as do cells in the nasal respiratory epithelium. So, the good news is, that if you do contract Covid-19 and lose your sense of small, it is not because the virus is rotting your brain.

This unfortunately does not imply that the virus couldn’t rot your brain. As reported on the WebMD site, a woman in her fifties showed up at the Henry Ford Health System in Detroit with a cough, fever and mental confusion that had arisen over the prior three days. Brain scans revealed an encephalopathy (swelling in some areas of the brain) as well as small areas of brain cell death. The presumptive diagnosis was that an “intracranial” cytokine storm occurred. That led to a breakdown of the blood-brain barrier that would normally shield the brain.

Numerous other cases of Covid-19 patients displaying neurologic symptoms — seizures, confusion and signs of encephalitis — have been reported in Italy and elsewhere. Neurological symptoms appear to be more common as Covid-19 becomes more severe. In fact, the CDC currently lists “new confusion or inability to rouse” as a warning sign that any ill person should seek immediate medical care.

Severe Covid-19 patients who have recovered after ICU treatment often report memory loss and other symptoms of post-traumatic stress. This has been termed ‘post-intensive care syndrome,’ and in severe cases, ‘post-ICU delirium’.

Less severe cases often report mild to moderate confusion, inability to focus and memory loss. Again this is not unique to Covid-19; neurastenia, was first coined by the American neurologist George Beard in 1869 to describe a condition ‘characterized by weakness, fatigue, lack of stamina, and exhaustion.’ Most of us have experienced first hand that, unlike the common cold, a full recovery from a good case of the flu, can take weeks, if not months.

Lungs

Which brings us to center stage, the pulmonary system. There’s an abundance of this ACE2 in cells in the lower lung, which may explain the high incidence of pneumonia and bronchitis in those with severe Covid-19 infection. ACE2 is widely distributed in lung tissue, and evidence suggests that many of the recognized comorbidities associated with severe Covid-19, such as hypertension, are the result of their having increased ACE2 expression in the lung.

ACE2 receptor abundance goes down in the elderly in all these tissues, but this in fact might place them at a greater risk of severe illness.This is because, as we’ve explored above, the ACE2 enzyme is an important regulator of the immune response, especially inflammation. It protects mice against acute lung injury triggered by sepsis. Turning off the gene for ACE2 actually led to severe lung damage in mice infected with H5N1, while treating mice with human ACE2 dampened lung injury. Thus, a fall in ACE2 activity in the elderly may partly be to blame for our poorer ability to put the brakes on our inflammatory response as we age.

Controversies

Many people with hypertension take a class of pharmaceuticals known as ACE inhibitors. ACE inhibitors block the conversion of angiotensin I to angiotensin II by inhibiting another enzyme named ACE1. The inhibitors were not felt to have any role in blocking ACE2. But a few years later, the second class of drugs was developed; angiotensin receptor blockers (ARBS), which blocked the action of angiotensin II further upstream by preventing angiotensin II from binding to specific receptor sites on the blood vessels and heart. ARBS, which have been shown to reduce the symptoms of congestive heart failure, lower blood pressure and protect the kidney from high blood pressure. They are often the first-line drugs used to treat these conditions.

A letter to the editor in The Lancet described the observation that Chinese patients who had high blood pressure, or diabetes, and who were taking ACE inhibitors, or ARBS had worse outcomes; with more severe infections and more deaths.The article implied that ARBS and ACE inhibitors elevated ACE2 levels, and that increased ACE2 facilitated more viral penetration into lung tissue. The paper concluded that taking these medicines could increase the number and severity of infections.

This caused a firestorm in medical circles, since millions of people take these drugs. However, it may well be a tempest in a teapot. If anything, reality may be quite the opposite: viral pneumonia seems to improve faster when patients are taking ACE inhibitors.

Therapeutics

A University of British Columbia research team has found a trial drug that effectively blocks the ‘cellular door’ SARS-CoV-2 uses to infect its hosts. The drug, called APN01, is a human recombinant soluble ACE2 (hrsACE2) that acts as a ‘decoy’ ACE2, and blocks growth of SARS-CoV-2 by a very imposing a factor of 1,000-5,000. The investigators used engineered replicas of human blood vessel and kidneys (‘organoids’) grown from human stem cells to demonstrate that the virus can directly infect and duplicate itself in these tissues. Clinical grade hrsACE2 also reduced the SARS-CoV-2 infection in these engineered human tissues, which has important implications for its utility as a system wide treatment. The drug is soon to be tested in clinical trials by the European biotech company Apeiron Biologics.

By virtue of their ability to target ACE2, a number of natural products may have benefit in combating or preventing Covid-19. In a network based study released as a preprint, the herbs Andrographis, Urtica (nettles), Sambucus (elderberry) and Astragalus, in addition to the nutraceuticals valproic acid and butyrate as potential candidates. As can be seen from the DataPunk Covid-19 Antiviral Database, many of these agents actually possess multiple actions.

Related Reading

Both the SARS coronavirus of 2003 and the novel coronavirus of 2019/20 are activated by TMPRSS2, thus can be blocked by TMPRSS2 inhibitors. SARSCoV2 uses ACE2 as a receptor for entry, and its spike protein is primed by TMPRSS2. Cells expressing TMPRSS2 show increased activation and replication of SARS-CoV.
Here is a prior blog that examines the link between ACE2 and TMPRSS2

Albert-László Barabási, a well-known network bioinformatics scholar, used machine learning at his lab to produce this image of the human interactome network that shows the targets of the COVID-19 virus, highlighted in red. Notice how the targets of the COVID-19 virus wrap around the whole human interactome. Image by Marinka Zitnik.

8 comments on “Covid-19: The ACE2 of Spades”

  1. Paul Nielsen Reply

    Is there something to the virus interference caused by flu vaccines that is playing a roll in all this? Sounds to me if the immune system and cell communication connection is broken the virus would replicate out of control until the only thing left to do was dump everything in the cytokine storm I keep hearing about. Please explain in simple terms as I am no doctor, it just seems like something to look into.

    • Peter D'Adamo Reply

      Maybe. Jury is out. Some respiratory viral infections appear to be potentiated by flu vaccine. Not sure about Covid-19. Doubt anyone is.

  2. DJ Reply

    I am doing what I can to understand the medical/scientific terminology but I can’t blame myself for being confused, as a layperson, if the medical profession is confused too.
    Does HBP by *itself* create an increased risk or susceptibility to COVID-19 if, hypothetically, HBP without medication doesn’t result in anything higher than around 150/90?
    Does lower blood pressure *with* either ACE inhibitors or ARBs carry a higher risk than slightly higher BP without it?

    • Peter D'Adamo Reply

      1.) HBP is an independent risk factor. 2.) I don’t know. 3.) Probably not.

  3. Regina Druz, MD Reply

    Peter, up to 19% of patient exhibit direct myocardial toxicity. Any info on that? Any predictors of that response? Patients succumb to fulminant myocarditis.

  4. Mike Reply

    Thank you for work and your website. I’d appreciate it if you would share your thoughts on the following statement I heard ….. “Elderberry juice increases production of cytokines TNF-a and IL-6. This substance is very effective against the common flu but may not be desirable for the H5N1 Bird Flu virus. It increases the production of toxic cytokines which could trigger a fatal cytokine storm.
    • Micro Algae: Chlorella and Spirulina: Both of these micro-algae act to increase the body’s natural production of the toxic cytokine TNF-a.
    • Honey: Honey increases production of toxic cytokines TNF-a and IL-6.
    • Chocolate: Chocolate increases production of both toxic cytokines TNF-a and IL-6. Chocolate contains Theobromide which is toxic to dogs and cats.
    • Echinacea: Echinacea increases production of cytokines TNF-a and IL-6. Although this is often beneficial to boost immunity with the common cold and certain strains of flu, research indicates that Echinacea should not be taken during this Flu pandemic because it may increase the risk of cytokine storms.
    • Kimchi: Kimchi increases production of both toxic cytokines TNF-a and IL-6 and therefore should not be taken.
    • Dairy Products and Bananas: Both dairy products and bananas naturally increase mucous production in the airways and respiratory system and as a result should not be taken.”

    Thank you for any feedback you can provide regarding this statement and Covid19.

Leave A Reply

Your email address will not be published. Required fields are marked *