Scientific Information about the COVID-19 (SARS-Cov-2) virus
There are many webpages repeating the essential information about how
to protect yourself by hand washing and social distancing. Here we look
a bit more into the science and draw some very practical conclusions
as well. The format is Question and Answer.
Viruses
are so small that even with unlimited magnification we would not be
able to see them in ordinary light because the wavelength of light is
too long. They are imaged using electron microscopy, but the best way
to visualise them, or anything at this molecular scale, is with an
interpretive illustration based on the electron microscope scan
together with detailed knowledge of the shape of molecules and the
electron clouds around them. This water colour painting by David
Goodsell is hard to beat in that respect. Quoting his caption (see
reference below) "It depicts a coronavirus just entering the lungs,
surrounded by mucus [green strings] secreted by respiratory cells,
secreted antibodies [the yellow three clubbed molecules] and several
small immune system proteins [orange]. The virus is enclosed by a
membrane that includes the S (spike) protein [big pink spiky clubs]
which will mediate attachment and entry into cells..."
Illustration by David S. Goodsell, RCSB Protein Data Bank; doi: 10.2210/rcsb_pdb/goodsell-gallery-019
What is COVID-19
It is the disease caused by the virus officially named
SARS-Cov-2, a member of the coronavirus family, which are all enveloped, positive strand RNA
viruses. This means that the virus has an outer membrane envelope of
phospholipids with
trans-membrane (glyco)proteins and an inner 'naked' single stand RNA
molecule formed in a way that acts directly as messenger RNA in a
eukaryotic cell (obviously, then, a human cell). That is a
horrifying thought as, once in the cell, it has direct access to the
cellular machinery (like having the admin. password on a computer).
This is because its RNA can be directly translated into protein by
ribosomes in the host cell (positive because it 'reads' from 5' to 3'
just like host cell mRNA).
Coronaviruses (so called because their trans-membrane envelope proteins
(spike glycoproteins) make them look a bit like little crowns under an
electron microscope) are common pests of mammals, including humans, for
whom most of them just cause a cold. Most of these are of the genus
alphaCoV or beta-CoV, SARS-Cov-2 is a beta-CoV. This little horror is
among several recent zoonotic (transferred from other animals) coronavirus and
appears to have originated from bats. It is closely related to SARS and
MERS, most closely to the bat SARS strain BatCov RaTG13 (96% genetic
identity), but recent work shows a pangolin might have been involved.
Genome details can be seen in
Wu et
al. 2020. The spike proteins embedded in the envelope have on them
a receptor binding domain (RBD) - this is the bit that attaches to a
target on the mammalian cell. Its RBD fits
like a key into the lock
that is the ACE2 receptor on the surface of many epithelial cells
throughout the body (especially the lining of arteries), but particularly vulnerable are those of the alvioli deep in the
lung (actually all the way down the respiratory tract and throughout the
alimentary canal, and it is emerging that intestinal problems can be
added to the respiratory, with the possibility of damage to the liver
bile ducts too - and the kidney's tubes).
The virons (individual virus particles) are about 120 nm in diameter (so
even very good masks won't keep them out - the point of
masks is to
block droplets of water and saliva in which virons may hitch a ride).
The spike (S) glycoproteins attach to an ACE2 receptor on an epithelial
cell. ACE2 (angiotensin converting enzyme 2) receptors are the chemical
transducers for the ACE2 enzyme that is attached to the surface of
these cells and functions to reduce blood pressure as part of a
homeostatic system (which is why it is a target for high blood pressure
management for those with cardiovascular diseases). It is a cruel irony
that this essential transducer is hijacked by the coronavirus. One
might think that blood pressure drugs that work by binding up ACE2
receptors (stopping them from reducing the amount of ACE2 around the
cells) would limit the virus's access to them. However, whilst the
action of ACE2 is protective of e.g. lung tissue, it turns out that the
blocker drugs actually reduce the chance of pneumonia (probably because
blood pressure is down regulated by increasing the leakiness of
capillaries, including those around lung alvioli. It's as if the virus
had already protected its king by castling that one.
What kills SARS-Cov-2 ?
On surfaces outside the body.
A recent study (Kampf et al 2020) examined the evidence for biocidal
agents against human coronavirus in general, when used on inanimate
surfaces (metal, plastic, etc.) and it is, at this stage, reasonable to
assume the results apply to SARS-Cov-2. The headline news is that top
of the list, 0.5% hydrogen peroxide and 0.1% sodium hyperchlorite
killed it within 1 minute. For most people (without access to
laboratory agents) that means household bleach works. Also 62-71% (or
more) ethanol works, but not less than that concentration and frankly,
it works much better at higher concentration. Most household cleaning
and disinfectant products that do not contain bleach use benzalkonium
chloride and some antiseptics use chlorhexidine, which are great on
bacteria and some viruses, but not too good on this one (not totally
useless, but you would not want to rely on them). Bleach has to be
quite strong (0.1%) because 0.05% did not work very well. So, we recommend
cleaning with strong bleach wherever it is acceptable to do so and if
not, then an oxidising agent, especially in combination with a
detergent. Look out for hydrogen peroxide (0.1%) for use on your hands as
an antiseptic (it is really the only available oxidising agent of
sufficient strength that is not unacceptably harmful to your skin).
Detergents disrupt the lipid membrane of the virus and work to prevent
it from sticking to your cells. Not proven, but we suspect that in
combination with a phenolic such as hexachlorophene, chloroxylenol,
chlorhexidine or triclosan, its action could be enhanced. Some
medicated soap formulations include these with detergents.
Inside the body.
Intense research on drug therapies is progressing so fast that what is
written here is likely to be already out of date. Still the front
runner (mid to late March 2020) is the antiviral Favipirivar (Fujifilm
Holdings and Zhejiang Hisun Pharmaceutical). This is a broad-spectrum
antiviral which acts through inhibiting RNA-dependent RNA polymerase
(RdRp) of RNA viruses. It has been used before - to treat avian flu in
Japan and Ebola in Guinea. It is currently undergoing clinical trials
(on patients). Also in clinical trials is the Gilead Sceiences
Nucleotide prodrug Remdesivir. This one had shown great promise in
vitro when combined with chloroquine phosphate (a malaria
drug). Other drugs are being investigated for
re-purposing (fastest possible track to the clinic) and in development,
including some very novel nano-particle systems such as micelles that
bind and capture virons using their spike proteins against them (rather
like synthetic immune cells) - a good example is the NanoViricides
system "like a venus fly trap for the virus" according to their press
release. Of course the longer term solution is a vaccine and several
are in development, but before that, we could expect direct antibody
treatments. One of the front runners in that technology is CytoDyn with
their monoclonal IgG4 called Leronlimab - it is a CCR5 antagonist.
Regeneron Pharmaceuticals are also making monoclonal antibodies and
nearing clinical trials. There are others.
Are viruses alive?
No, not according to our definition of life - the question above would
be more accurately put as "what deactivates virons". They are
obligatory
parasites, but that in itself does not stop them being alive. The
reason is that whilst other parasites depend on their host to provide a
particular environment in which to flourish (for example providing
essential nutrients), viruses require their host to provide parts of
the autopoietically
internal
system. In other words, for a virus, the
(M,R)-system is not complete,
they do not have what it takes to be closed to efficient causation,
their causal loops are not closed and they cannot function
internally as a whole without their
host. Even though they can reproduce, evolve and, within a host cell,
perform some kinds of metabolism, they do not fit the I-F-B definition
of life. The key difference between living and non-living parasites is
that the former need their host only for external resources, whilst the
latter require them to provide some missing internal parts (they are
not causally whole). - This question is now the subject of a short article published by
United Academics at
https://www.ua-magazine.com/are-viruses-alive/
How do we model the epidemic?
First, to get the latest high quality, responsible, quantitative
reporting, I think it would be hard to do better than than the John
Hopkins University
dashboard
(announced
by Dong and Gardner, Feb. 2020), but it is entirely empirical (just
gathering the figures and presenting them). Modelling is an attempt to
go beyond that by representing the informative features of the
dynamics, with a view to forecasting future outcomes. The foundation
for most models for epidemic forecasting is the S-I-R differential
equation system. The letters stand for Susceptible, Infected and
Removed - see below. An elaboration of this approach lay behind the
highly influential paper from Imperial College
(London University) that is credited with changing public policy in the
UK and to some extent in other countries, notably the USA. On the web,
there are lots of demonstrations of simple S-I-R model systems and
explanations of the thinking behind them. I just picked
this one for the time being.
The S-I-R model represents the average dynamics of the infection in a
large population and most of the practical models being used to advise
policy makers are S-I-R with some of the generalities made more
specific. Susceptible people are available to the virus to infect: the
more of them there are, the bigger the outbreak. Infected people were
susceptible and have now got the virus, the number of infected depends
on the infection rate (related to, but not the same as how quickly the
infection spreads) and also on the rate of removals. The overall
dynamics is then a flow rate from S to I and from I to R. Let us
recognise that R (removed) includes those who have recovered and those
that have died and also those who have become inaccessible to the virus
by isolation. The rate of increase of infected cases has to decline as
R increases relative to S because the virus is then running out of
people to infect.
This is why it is such a good idea to stay at home and socially isolate
- don't let the virus see you, be one of the R group and help lower the
infection rate (as well as obviously protecting
yourself). Early in the outbreak, the UK Government was talking
of maximising "
herd immunity"
to defeat the virus. They seem to have misinterpreted R as recovered
(and therefore immune), forgetting that R includes also those killed by
the infection. Thankfully the UK Government quickly changed their
strategy and adopted a phased lockdown, with the effect of (mostly)
hiding susceptible people from the virus. Much better!
The three most important elaborations of the model are: a) to represent
spread in geographic space; b) to represent contact rates and therefore
transmission probabilities among different categories of people and c)
to disaggregate the population into specific groups (age and sex,
certainly, perhaps also economic class or similar). We already know,
for example, the differences in incidence of severe disease and
mortality among age groups and sexes (males are quite a lot worse off,
so are people who vape or smoke (though we did not find any significant
stats on smoking yet) and it is thought that those with high blood
pressure are at greater risk of severe disease (could be to do with the
ACE2 access point) and blood group even has an effect (we will point
you to the details on this as soon as we get the chance).
How does SARS-Cov-2 work ?
The RNA inside the virus acts directly as messenger RNA (mRNA) in the
host cell (it is class IV in the Baltimore system, named after its
author, Nobel Laureat (1975) David Baltimore who discovered the reverse
transcriptase process and thereby retroviruses, contributing much basic
science to defeat AIDS). Once inside the host cell, floating in the
cytoplasm, the virus RNA strand inevitably encounters one of the host
cell ribosomes. Despite it being alien to the cell and not capped in
the correct way for reading, it seems the way it is folded (like a
string of beads dropped onto the table) enables it to interact with the
ribosome and con it into reading and translating the RNA sequence. Unlike our mRNA, it
codes for every protein it requires in one go (it is monocistronic), so
the protein product coming out of the feckless ribosome is a single
giant
polyprotein. On the
face of it this cannot do anything because although it contains all the
functional proteins, structural and enzymes, they are all joined
together and unable to work like that. What is needed is an enzyme that
can chop this polyprotein into the pieces in the right places, so the
individual functional proteins are released: it needs a protease. The
problem is that its own (virus encoded) protease that does this job is
itself part of the polyprotein. The first job of this protease, in a
mind boggling act of
bootstrapping,
is to cleave itself out of the polyprotein. Such self cleavage is
relatively common in RNA (referring to self-splicing introns), but
quite something when a protein molecule does it. Once the virus
dependent protease has cut itself out, it chops the rest up. One of the
resulting functional proteins is a virus encoded RNA polymerase, as the
name suggests it is an enzyme that makes RNA (it is therefore an
RNA-dependent RNA polymerase).
This enables the virus to replicate within the hapless cell because
this enzyme uses the cell's own stock of nucleic acids to synthesise
negative stranded RNA, which can then be used a as template to make
thousands of copies of the virus positive stranded RNA. This molecule
is the target for the drug Favipirivar mentioned above.
What makes it a serious illness in a fraction of cases ?
On current figures (which could change a lot as mass antibody testing is introduced - see
Lourenco et al (24-03-20), with response from Anna Seyburn in the
British Medical Journal and Carson Chow’s response
here),
it seems roughly 20% of those contracting COVID-19 suffer a serious
illness. Of these, a fairly high proportion are starting mild and
(often after about 5-7 days) go down hill very quickly. Clinical
features indicate the reason is a derangement of the immune system and
quite likely at least a big part of that is a runaway 'cytokine storm'
of the homeostatic communications among immune cells. One of the key
diagnostic features is the ratio of neutrophils to lymphocytes [
NLR]
(a healthy adult has 4-5 thousand neutrophils and between 1.5 and 3
thousand lymphocytes / mm blood: a ratio of around 2). On presentation
at hospital, the ratio can be around up to 3 for someone who is
going to get better*; above that and towards 10 (even in young
patients), they are likely to need high-dependency care and much more
than 12, they will be on the respirator, if it is over 20, they are
very unlikely to survive (all rough figures, - listen to podcast from
“This Week in Virology” for this insight: link below). The explanation
is still a matter of active research, but the imbalance of immune cell
types (more than these two, but they are key indicators) is strongly
associated with serious derangement of the inter-immune cell signalling
molecules cytokines, especially some of the interleukins (of which IL6
is receiving particular attention). This, then, is clearly a case
of the virus messing up communications and information processing in
the immune system (see the section on
homeostasis
in our autopoiesis page for an introduction to cell signalling
information in general). I hope to write more on this topic in the next
few days (its 31st March today).
* The
orignal scientific study predicts 50% severe illness if NLR > 3.13 and age > 50.
Tan et al
(27th March) showed pathologically low lymphocyte counts predict
severity and bad prognosis in the COVID-19 disease. They considered
several plausible hypotheses for the loss of lymphocytes. Subsequently
it is becoming apparent that at least one of these plays a critical role and is a target for
drug therapies. Quoting them directly:
“
Inflammatory cytokines continued to be disordered, perhaps leading to
lymphocyte apoptosis. Basic researches confirmed that tumour necrosis
factor (TNF)α, interleukin (IL)-6, and other pro-inflammatory cytokines
could induce lymphocyte deficiency.6” [note citation hyperlink takes you to Tan et al. where you can follow to the reference given below]
6. Liao, Y. C. et al. IL-19 induces production of IL-6 and TNF-alpha
and results in cell apoptosis through TNF-alpha. J. Immunol. 169,
4288–4297 (2002).
Interleukins (a class of cytokine), especially IL6 are now implicated in creating the severe form of COVID-19. See e.g.
Cennimo (March 30th) .
References
Kampf, G. Todt, D., Pfaender, S. Steinmann, E. (2020). Persistence of
coronaviruses on inanimate surfaces and their inactivation with
biocidal agents. Journal of Hospital Infection. 104. 246-251.
Wu, F. et al. (2020). A new coronavirus associated with human respiritary disease in China. Nature (on line).
Recommended short video It is on youtube and although I was sceptical at first, I watched it and think it is brilliant.
Quick Links and Resoures
This is fast moving science, so, especially for professionals and those
with more advanced interest, here are some resources on the web.
The World Health Organisation (naturally).
https://www.who.int/health-topics/coronavirus
Wikipedia (of course)
https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2
CDC COVID-19 page Very useful especially for clinicians interested in the USA approach.
Medscape news collection (a great place to get the latest from clinic and lab)
https://www.medscape.com/resource/uk-coronavirus
Genetic Engineering & Biotech News Updates on progress of development of treatments (all kinds everywhere).
https://www.genengnews.com/a-lists/how-to-conquer-coronavirus-top-35-treatments-in-development/
Nature Biotech. article on fast-tracking antiviral therapies
https://www.nature.com/articles/d41587-020-00003-1
Updated in this bulletin:
https://www.nature.com/articles/d41587-020-00005-z
RND systems - developing diagnostic tests, assays and treatments. Especially this
bulletin
https://www.rndsystems.com/resources/articles/ace-2-sars-receptor-identified
https://www.rndsystems.com/products/discover-products-answers-about-sars-cov-2-covid-19
This Week in Virology With News (like a podcast) from the clinical coal-face
http://www.microbe.tv/twiv/