An Achilles heel
Following on from our first article last month on key reasons why the UK government strategy & response have been so wrong and caused the deaths of tens of thousands of people, this article outlines the key roles of vitamin D, endothelial nitric oxide synthase (eNOS or NOS3) and nitric oxide in attenuating the pathogenesis of SARS-CoV-2.
In early July we wrote about the relevance of sunlight as one of the three key environmental factors (the other two being ambient temperature and humidity) that created the ideal conditions for the spread of SARS-CoV-2 as a seasonal coronavirus.
SARS-CoV-2 has several potential Achilles heels, something the UK government would refuse to believe on account of ‘the coronavirus’ not having any legs. In terms of their use in antiviral treatments, these include the reliance upon TMPRSS2 and furin for cellular entry and the role of the nonstructural protein 14 3′-to-5′ exoribonuclease (nsp14-ExoN) in proofreading and defective viral genomes. However, as a countermeasure SARS-CoV-2 has a basic Achilles heel that is readily available and in abundance: vitamin D.
Vitamin D
The principal source of vitamin D in humans is creation through exposure to sunlight, specifically UVB radiation, which causes the skin to synthesise cholecalciferol, which then converts to calcifediol, which in turn converts to calcitriol, which is ‘active’ vitamin D. It can also be ingested through supplements and some foods, although only a relatively small number are naturally rich in it (mainly eggs and oily fish) so dietary intake can be difficult. Some cereals and bread are marketed as being high in vitamin D but this is through them being enriched artificially.
Vitamin D performs a wide range of functions, including being a vasodilator and regulator of the cardiovascular system. Vitamin D deficiency – categorised as a level of <12ng/ml (12ug) – causes hypertension, left ventricular hypertrophy and endothelial dysfunction as well as contributing to kidney disease and diabetes. There is a very high positive correlation between the proportion of a population with vitamin D deficiency and that population’s SARS-CoV-2 mortality rate, especially in many European countries where vitamin D deficiency is rife. This sounds surprising in 21st century developed economies but it easily explained by individuals leading increasingly sedentary and indoor lives, exacerbated by the pubic health messages about sunlight being bad for you. In recent years, with the sun having become the killer corona of death, is it any surprise that coronavirus was labelled the killer virus of death simply because the virion looks a bit like a sun?
As with just about everything biochemical, too much is bad but so is too little and we are now seeing the consequences of years of being told to cower away from the sun.
Endothelial nitric oxide synthase
eNOS is one of a family of three enzymes (enzymes are essentially proteins that are catalysts or triggers to make or help make ‘other stuff happen’) with the others being neuronal (nNOS or NOS1) and inducible (iNOS or NOS2). eNOS is present in the endothelium, a thin layer of cells that lines the inside of blood vessels and along with nNOS and iNOS, it is responsible for the synthesis of nitric oxide.
Nitric Oxide
Not to be confused with N2O (which is nitrous oxide, aka laughing gas or a heavily-Halfordised Vauxhall Corsa), NO or nitric oxide is a member of the reactive oxygen species group of molecules and plays a part in the regulation of a number of biological functions. In respect of the cardiovascular system is helps to control blood pressure, the effective function of blood vessels and the prevention of build-up of fatty deposits in the arteries. Low levels of NO production and the related impact on vasodilation can lead to hypertension, hypercholesterolaemia and diabetes [Förstemann and Sessa, 2011].
Relationship to ACE2
The activation and stimulation of the ACE2→ Angiotensin1-7→ Mas receptor axis causes increased NO production which is good however endothelial dysfunction, i.e. the inability to produce NO, inhibits this stimulation. As SARS-CoV-2 binds to ACE2 receptors on epithelial cells, those with conditions such as hypertension, obesity and diabetes will see their ACE2 function inhibited by cellular damage. Therefore;
- the ACE2→ angiotensin1-7→ Mas receptor axis is not stimulated.
- the counter-function ACE→ angiotensin II→ AT1 receptor axis is stimulated.
- NO production is reduced.
These are each negative factors in isolation but their effect is compounded when they combine.
Breathe In, Breathe Out
NO is synthesised particuarly in the paranasal sinuses and nasopharynx [Mantel et al, 2020]. It stimulates mucal secretion which helps clear the respiratory tract of invasive particles [Nagaki et al], whether they are dust, pollutant particles or – yes, you’ve guessed it – pathogens such as virions. Rita et al posited that nasally-produced NO is an element of the innate immune system specifically designed to pick up the presence of pathogens in the human airway. This is of course crucial as the TMPRSS2 and furin enzymes in the human airway are how SARS-CoV-2’s spike glycoprotein is activated through its furin cleavage site. In other words, NO is attacking the virion as soon as it is present. Not just through the desire to expel it by exhalation (still like the idea of strapping a piece of cloth over your face so you can keep on re-inhaling over & over all day long any virion-infected mucal excreta that you would normally freely and immediately exhale?) but also by actively targeting the virion.
NO expresses antimicobial properties to protect the lungs [Nathan et al, 1994], [Jung et al, 2013] as well as inhibits viral replication by messing with SARS-CoV-2’s amino acids [Xu et al, 2020], likely around nonstructural proteins 3 & 4.
Conclusions
It is important to highlight that neither vitamin D nor NO are silver bullets.
Vitamin D does not prevent anyone from getting SARS-CoV-2 in the first place, something often touted as a putative justification by those seeking to explain why it hasn’t been suggested as a remedy previously. However, nobody has said and nobody is saying it prevents infection.
A low level of vitamin D, especially deficiency, makes it more difficult for the body to effectively fight the virus. Conversely, just a normal level of vitamin D can make an individual up to 10.4x more resilient in dealing with any infection, i.e. it is dealt with effectively by the innate immune system without the any need for the adaptive immune system.
Excessive NO is not automatically good and can be inflammatory, especially in relation to uncontrolled iNOS synthesis which is a main cause of septic shock. But again conversely, too low a NO level prevents the initial response to the virion in the human airway and endothelial dysfunction – causing low NO production – is a factor in hypertension, hypercholesterolaemia and atherogenesis.
A healthy level of vitamin D means healthy eNOS regulation which means healthy NO synthesis.
A healthy level of NO increases the body’s initial response to the detection of virion in the human airway and produces a counter-function to the activation of the virion through its furin cleavage site.
Low levels of NO in the human airway increase the chances of developing COVID-19 symptoms, especially in those with comorbidities, who are themselves already susceptible to low levels of NO synthesis through endothelial dysfunction.
Healthy NO production also attacks the virion’s genome by targeting its ability to replicate.
What is a healthy level of vitamin D?
Vitamin D deficiency is <12ng/ml (12ug). A prudent level is at least 25ng/ml (25ug), perhaps 30ng/ml (30ug). That’s about 1,000 IU. Don’t exceed 100ng/ml (100ug), which is around 4,000 IU. Taking a supplement at a level somewhere between 25ng/ml – 100ng/ml for a couple of weeks and then reverting to the lower level as a constant will support your immune system, especially given that we are going into fewer hours of daylight and therefore lower capacity to create vitamin D through natural synthesis.
Some research also suggests that breathing through your nose is better than through your mouth as this stimulates NO synthesis in the paranasal sinuses and nasopharynx, especially when sleeping. Changing from mouth to nose isn’t easy if you’ve always tended to do the former but even trying to cut down on mouth-breathing by making a conscious effort to adopt the latter is a move in the right direction that will come more naturally over time.
Along with a good night’s sleep – NO works particularly well when you are asleep plus the immune system recharges itself – just a healthy level of vitamin D makes you many times more effective at dealing with any pathogen in general and SARS-CoV-2 in particular. It is also a much more effective action to stay healthy than following government advice.
It is possible to test for your vitamin D level, with home testing kits costing from around £30. If you do feel the need to test yourself for something, then do it for vitamin D as this is far more useful and beneficial to your health in general and ability to manage any SARS-CoV-2 infection in particular. That’s assuming you are one of the few remaining people who hasn’t yet had it, despite the government wanting everyone to believe that it is still out there and nobody must ever get it.
Do not panic. Do not worry. Do not follow government advice.