The Evidence which Suggests that This Is No Naturally Evolved Virus
A Reconstructed Historical Aetiology of the SARS-CoV-2 Spike
Birger Sørensen, Angus Dalgleish & Andres Susrud Immunor & St Georges
University of London
To discover exactly how to attack SARS-CoV-2 safely and efficiently, our
vaccine candidate Biovacc-19 was designed by first carefully analysing the
biochemistry of the Spike. We ascertained that it is highly unusual in several
respects, unlike any other CoV in its clade. The SARS-CoV-2 general mode
of action is as a co-receptor dependent phagocyte. But data shows that
simultaneously it is capable of binding to ACE2 receptors in its receptor
binding domain. In short, SARS-CoV-2 is possessed of dual action
capability. In this paper we argue that the likelihood of this being the result
of natural processes is very small. The spike has six inserts which are
unique fingerprints with five salient features indicative of purposive
manipulation. We then add to the bio-chemistry a diachronic dimension by
analysing a sequence of four linked published research projects which, we
suggest, show by deduction how, where, when and by whom the SARS-
CoV-2 Spike acquired its special characteristics. This reconstructed
historical aetiology meets the criteria of means, timing, agent and place to
produce sufficient confidence to reverse the burden of proof. Henceforth,
those who would maintain that the Covid-19 pandemic arose from zoonotic
transfer need to explain precisely why this more parsimonious account is
wrong before asserting that their evidence is persuasive, most especially
when, as we also show, there are puzzling errors in their use of evidence.
Introduction: Why does this matter?
No-one has ever produced a safe and effective vaccine against a
coronavirus. In the context of a forthcoming paper addressing contingency
actions cognizant of this fact, the potentialities for 'trained immunity' from
'new old friends' in the form of Bacillus Calmette–Guérin (BCG),
Microbacillus vaccae (IMM-102) and most especially Microbacillus obuense
(IMM- 101) by stimulating the innate immune system and especially Delta
Gamma T cells are explored; and a salutary review of failed vaccine
programmes is included (Kleen et al., 2020). On 28th April 2020, Nature
published a graphical guide to eight conceptual approaches featuring in
current explorations of around 90 vaccine development programmes
intended to counter SARS-CoV-2 (Callaway, 2020).
We have just (2nd June 2020) published Biovacc-19 in QRB-Discovery: a
candidate vaccine for this daunting task (Sørensen et al., 2020). Its mode of
action is unique and therefore is not included in the Nature review. In our
paper we gave reasons why the virus vector or RNA vector based
approaches that are the basis of the eight methodologies reviewed in
Nature are unlikely to prove immunogenic and why either, but especially
RNA vectored models, may carry significant risk of Antibody Dependent
Enhancement (ADE). As we have detailed in QRB-D, we have seen such a
story before over thirty years in the failure of all three mainstream vaccine
approaches to HIV, which we predicted but were disbelieved.
As with our HIV vaccine, the methodology underpinning Biovacc-19 first
analysed fully the virus target. In this case we published the general mode
of action for infectivity of SARS-CoV-2. Doing this took us into a
fundamental exploration of the biochemistry and structure of the SARS-
CoV-2 Spike which is highly singular, possessed of features that we have not
seen before and which are not present in other SARS viruses of that clade.
We posited that the SARS-CoV-2 general mode of action is as a co-receptor
dependent phagocyte. But unusually, simultaneously, data shows that it is
capable of binding to ACE2 receptors in its receptor binding domain. In
short, SARS- CoV-2 is possessed of dual action capability. How do we think
this was made possible? That is the subject of this paper. We shall argue
from evidence below that the likelihood of this being the result of natural
processes is very small.
The co-receptor dependent phagocytic general method of action for
infectivity and pathogenicity of SARS-CoV-2 appears to be specifically
related to cumulative charge resulting from inserts placed on the surface of
the Spike receptor binding domain, right next to the receptor binding motif.
That SARS-CoV-2 has charged inserts is not in dispute (Zhou et al., 2020)
What we have shown that is new is that the SARS-CoV-2 Spike carries
significant additional charge (isoelectric point (pI) pI=8.2) compared to
human SARS-CoV Spike,( pI = 5.67) and the implications thereof. Basic
domains - partly inserted, partly substituted amino acids and partly
redistributed from outside the receptor binding domain - explain the salt
bridges formed between the SARS-CoV-2 Spike and its co-receptors on the
cell membrane. We comment further on the significance of this in the next
section.
1
Puzzling features
An influential paper was published in Nature Medicine on 17 March 2020.
Andersen et al observed that several mutations have occurred in the
receptor binding domain of SARS-CoV-2. These, they suggested, therefore
sustain an hypothesis of natural evolution (Andersen et al., 2020). We do
not agree. We do agree that it is indeed correct that several such mutations
are to be seen and in a forthcoming companion article to this one, about
three other viruses of interest, we will discuss further Andersen et al's
evidence and argumentation in that context. But here we observe only that
the contention that it is improbable that Covid-19 emerged through
laboratory manipulation of a related SARS-CoV-like coronavirus because the
ACE2 binding is not ideal is weakened because Andersen et al cite two
authorities which actually say the reverse of what they say that they say.
Wan et al are cited by Andersen et al but offer them no support (Wan et al.,
2020). Wan et al say, correctly in our view, that computational structural
modelling of complex virus-receptor interactions can be used for structural
predictions and that such models can potentially be used for Gain-Of-
Function modelling. It is well known that models have been developed from
data generated in animal model systems such as the palm civet. Wan et al
say that the SARS-CoV-2 binding to the ACE2 receptor confirms the
accuracy of the structural predictions. Therefore the data and conclusion in
Wan et al contradicts Andersen et al's opinion that it is improbable that the
virus could have emerged through laboratory manipulation.
There is a similar problem with (Sheahan et al., 2008). This deals with
research on a civet strain SZ16 and the infective strain SARS-CoV Urbani.
These strains were used to create a chimeric virus icSZ16-S. Sheahan et al
go on to explain that by in vitro evolution of the chimeric virus icSZ16-S on
human airway epithelial (HAE) cells in the lab, they have been able to
produce two new viruses binding to such HAE cells. Therefore this reference
supports the very opposite of the Andersen et al hypothesis. We are
immediately wary of any paper containing such egregious errors.
Our discovery of the high pI number, the high accumulated charge and how
it comes about, in the course of our bio- chemical analysis, suggested
several features which individually seem unlikely to be the result of natural
evolution and which, taken together, and applying Occam's Razor to hone
the most parsimonious hypothesis, make natural evolution a less likely
explanation than purposive manipulation, specifically for Gain of Function.
Figure 1: The identified inserts examined in the PDB 6VXX electron
microscopy structure (Walls et al., 2020) The sequences highlighted in red
could not be found in the cryo-electron microscopy structure data. The 6
aligned sequences in Fig. 1 in (Sørensen et al.,2020) are underlined in the
missing sequences. Bold amino acids indicate first and last amino acids
used to build the structure where the missing part is in between. Insert 6 did
not have the same sequence in 6VXX as in the reference Sars-CoV-2
sequence. The authors stated that a designed mutated strain lacking the
furin cleavage site residues was used.
2
To recapitulate Fig 2 from our vaccine paper, there are 6 inserts which make
the SARS-CoV-2 Spike structurally special. They are unique fingerprints of
the SARS-CoV-2 Spike which deserve to be highlighted in support of this
view; and there are five salient features that strengthen the case for
purposive manipulation in the laboratory.
1. A major part of the spike protein has human-like domains with matured
transmission adaption. Blasting the Spike protein with a rolling window of 6
amino acids showed that 78.4% of 6 amino acid windows are human like.
This means that with nearly 80% of the spike protein has a built-in stealth
property by having high human similarity. Therefore, it is remarkably well-
adapted virus for human co-existence. Such high human similarity also
implies a high risk for the development of severe adverse events/toxicity and
even Antibody Dependent Enhancement (ADE) unless specific precautions
are taken when using the Spike protein in any vaccine candidate:
precautions that might not suggest themselves to designers employing
conventional methodologies and innocent assumptions about the target
virus, lacking our detailed anatomisation of it. Furthermore and significantly,
Zhan et al also note that, surprisingly, this characteristic is present from the
very first isolate (Zhan et al, 2020). This is something that does not sit well
with an hypothesis of natural evolution.
2. The Spike displays new amino acid inserts with condensed cumulative
charge, all of which are surface exposed (please refer to the reproduced
figure from the vaccine paper, above). This is a most significant finding as
we mentioned in opening. Being physically located on the surface of the
Spike protein greatly increases the infectivity and pathogenicity of the virus,
enabling these inserts to participate in binding to co- receptors/negatively
charged attachment receptors or even, as we have discovered, to the
negatively charged phospholipid heads on the cell membrane. Such a result
is typically the objective of gain of function experiments to create chimeric
viruses of high potency. Therefore this is a strong indicator of manipulation
3. The concentration of positive charge is on the receptor binding domain
near the receptor binding motif at the top of the Spike protein. As with (2)
this is more elegantly explained by an hypothesis of purposive manipulation
than one of natural evolution. As can be seen in Figure 2 (side view) of the
Spike trimer, the majority of the positive charged amino acids are located
near or on the top of the spike protein giving the receptor binding domain a
pI=8.906, while the Cov-2 specific Cys538-Cys590 bridge brings in
additional charge from 526-560 (with even higher pI=10.03) via the Cys391-
Cys525 to positions right next to the receptor binding motif (where the
ACE2 receptor is located). It is this which facilitates the dual mode
capability, allowing binding to ACE2 and/or to co- receptors/attachments
receptors. We posit that such ACE2 independent attachment and infectivity
is happening and is evidenced clinically by the Covid-19 disease pattern. It
is also reported by Zhou et al (2018). The receptors that are the most likely
to be involved are CLEC4M/DC-SIGN (CD209) – see discussion point (5)
below.
3
Figure 2: The positive charged domains associated with cysteine loops
Cys131-Cys166, Cys336-Cys361, Cys391-Cys525, Cys538-Cys590. As can
be seen, there is a high concentration of positive charged surface exposed
amino acids within the receptor domain next to the receptor binding motif at
the top of the spike. The location of the positive charged amino acids in red
circles on the right-hand side of the figure points out their surface exposure
making them available for cell attachment as discussed in (5) below. Insert 2
(HKNNK) in Figure 1 above is located within the Cys131-Cys166 loop but
was omitted in the Cryo-EM structure shown in dashed lines (Walls et al,
2020). However, charged amino acids belong to the hydrophilic group of
amino acids and are most likely surface exposed.
4. The Spike is so configured that it can bind to cell tissue without use of the
ACE2 receptor. Clinically it is widely observed that the Covid-19 virus
compromises the functions of olfaction and bitter/sweet receptors,
erythrocytes, t-cells, neurons and various tissues such as intestine epithelia.
These different targets do not engage and use ACE2 receptor binding. The
concentration of high positive charge in and around the top of the Spike
protein and the potential to use opposite charged attachment-/co-receptors
can facilitate binding and infection in the general mode of action for
infectivity that we published in detail in QRBD. In 2018 Zhou P et.al. 2018
found that a new Corona virus which they named SADS (Swine Acute
Diarrhoea Syndrome) could infect the intestine and kill piglets without use of
ACE2, aminopeptidase N (APN) or dipeptidyl peptidase 4 (DPP4) receptors.
[9] We have done a blast analysis of the SADS Spike S1 protein and could
find no trace of ACE2 RBM. The significance of this will become clear in the
next point and the next section.
5. Location and concentration of charge on the attachment receptor
CLEC4M/DC-SIGN (C-type Lectin domain family 4 member M (CLEC4M)/
Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-
integrin(DC- SIGNR) also known as CD209) (Marzi et al., 2004). Analysis of
the CLEC4M attachment receptor shows an overall pI=5.23 where the C-
type lectin tail 274-390 has a pI=4.4. However, due to the two disulfide
bonds Cys296- Cys389 and Cys368-Cys381 the C-terminal part of the tail
is pulled back to a domain around position 296. This condensed negatively
charged domain is ready for formation of salt-bridges with similar
condensed opposite charged amino acids structures on the S1 RBD of
SARS-CoV-2. This finding is fascinating and significant for a different reason
to the others. It is not about Spike manipulation itself: in the next section we
will explain that and how we believe that these capabilities were developed
between 2008 - 2015. This finding points to something else: a trial to
demonstrate a newly discovered attachment/co-receptor by field testing
and verification. The context was the 2018 Swine Acute Diarrhoea
Syndrome (SADS) outbreak in Guangzhou province.[10] Assuming that the
Wuhan Institute of Virology team had discovered the functionalities of
CLEC4M/DC-SIGN/CD209 receptors in the new SADS-CoV isolate and the
fact that it could bind to positive charge (Ref:
https://www.uniprot.org/uniprot/Q9NNX6 (CD209) and
https://www.uniprot.org/uniprot/Q9H2X3) and that they wanted to do a field
test of the described functionalities, the best conditions for doing so would
be in connection with an ongoing viral infection. If this SADS originally did
not have a ACE2 receptor binding motif
4
(RBM), then a binding capacity verification of these attachment receptors
could be done straightforwardly. But if SADS did have an ACE2 RBM, then it
would be necessary to remove or disable the RBM of the Spike protein on
this CoV isolate and execute the experiment in piglets including the formal
Cox postulate verification of infection as described in the 2018 paper.
We postulate that there are 2 charged domains on SADS that are likely to
contribute to attachment receptor binding located in domains 330-360 and
540-560 respectively. Recollect that we have identified a similar highly
charged structure on SARS-CoV-2 within the edge of the RBD domain (526-
560) with pI=10.03 which is brought right into the core of the RBD (to
approximately position 400) by Cys-Cys bridging of the domain (538-590).
This domain can contribute binding similar to that which can be observed
for SADS. This new Cys-Cys property inserted into the SARS-CoV-2 Spike
does not exist in SARS-CoV and hence could not provide such charge
enhancement onto the RBD and co-receptor binding by natural evolution.
Taken all together, we suggest that our research findings on the general
mode of action for infectivity of SARS-CoV-2 and the further puzzling
features just mentioned, justify the question of the historical aetiology of
these manipulations.
We did not need to address this issue diachronically for the purposes of
vaccine design. However, it is important for a soundly based understanding
of the present and potential future epidemiology of the Covid-19 pandemic
and for strategies for its management. Therefore to our earlier amino-acid
level of biochemical analysis we now add here a forensic analysis of
published research literature concerning SARS-CoV-2. We will extend this
type of analysis to three other viruses in the companion article.
Since, regrettably, international access has not been allowed to the relevant
laboratories or materials, since Chinese scientists who wished to share their
knowledge have not been able to do so and indeed since it appears that
preserved virus material and related information have been destroyed, we
are compelled to apply deduction to the published scientific literature,
informed by our own biochemical analyses. We refute pre-emptively
objection that this methodology does not result in absolute proof by
observing that to make such a statement is to misunderstand scientific
logic. The longer the chain of causation of individual findings that is shown,
especially converging from different disciplines, the greater the confidence
in the whole. We posit that the evidence below attains a high level of
confidence.
A sequence of four linked research papers is explained
A comprehensive review of the relevant literature shows that a substantial
amount of directly relevant gain-of function research has been undertaken.
Four studies are especially noteworthy. They are linked in two ways:
scientifically, in that the third and fourth build upon the results of the first
and second, and in continuity of the institution and personnel across all four.
The Wuhan Institute of Virology is a key collaborator in all these projects and
Dr Zheng-Li Shi is one of the Institute's most experienced virologists and
bat specialists. She is a common thread through all the key research
projects.
1. In 2008, Dr Shi was in the team whose research was an enabling pre-
cursor to the two linked gain-of-function projects which lead to SARS-CoV-
2's exact functionalities, including functionalities discovered via SADS and
potentially field-tested in the 2018 study as suggested above. The 2008
Ren W et al project successfully demonstrated technical capabilities to
interchange RBD’s between bat SARS-like and human SARS viruses: “... a
minimal insert region (amino acids 310 to 518) was found to be sufficient to
convert the SL-CoV S from non-ACE2 binding to human ACE2 binding,
indicating that the SL-CoV S is largely compatible with SARS-CoV S protein
both in structure and in function. The significance of these findings in
relation to virus origin, virus recombination, and host switching is discussed"
(Ren et al, 2008). Dr Shi is next a lead author of the second paper in this
sequence, (Hou et al, 2010) and a co-author and the senior Chinese author
of the third, (Menachery et al, 2015). She is also a co-author of the fourth
(Zhou P. et al, 2018)
2. In 2010 scientists from the 'Special Viruses' section of the Wuhan Institute
of Virology were engaged in 'gain of function' experiments, jointly with
international collaborators, to increase SARS-CoV infectiousness for
humans. They used an HIV pseudo virus to express seven bat ACE2
receptors and compared their binding properties to human ACE2 receptors
in order to pick the best for further optimizing a SARS-like coronavirus’s
ability to bind to human cells. They also found that some bat ACE2 receptors
are very close to human ACE2 receptors. This study provided a model
system for testing the most infectious of SARS-CoV-like viruses which
already had been selected in a vast survey of Chinese bat populations
between 2005 – 2013.(Xu L et al, 2016). These viruses were potentially
5
infectious to humans via the ACE2 receptor. Further new viruses were
identified between 2012-2015 (Lin et al,2017).
3. In 2015 scientists from the 'Special Viruses' section of the Wuhan Institute
of Virology were engaged in 'gain of function' experiments jointly with a
majority team from the University of North Carolina Chapel Hill. Together,
they manipulated bat viruses to create a mouse adapted chimeric virus
SHC014-MA15 which binds to and can proliferate on human upper airway
cells (2B4 Calu-3 - a cell line contributed by Chapel Hill): ("group 2b viruses
encoding the SHC014 spike in a wild type backbone can efficiently utilize
multiple ACE2 receptor orthologs, replicate efficiently in primary human
airway cells, and achieve in vitro titers equivalent to epidemic strains of
SARS-CoV"). We suggest that it is a high priority in further investigations to
ascertain precisely from Chapel Hill lab records the exact donor provenance
of 2B4 Calu-3. The lead Wuhan scientist, who provided the CoV material,
was Dr Zheng-Li Shi ("provided SHC014 spike sequences and plasmids").
We note that what is described here are, in fact, precisely SARS-CoV-2
properties. In vivo experiments at Chapel Hill replicated the chimeric virus in
mouse lung which showed significant pathogenesis which was the opposite
of what the team had expected ("the creation of chimeric viruses like
SHC014-MA15 was not expected to increase pathogenicity"). Menachery et
al reported that it may be hard to develop a vaccine against SHC014-MA15.
We can see, therefore, that the 2015 experiment advanced the 2010 work by
perfecting in animal trials a virus optimised to infect the human upper
respiratory tract. The 2015 authors were well aware that the chimeric virus
which they had created was very dangerous because they discussed this
fact. Of the opportunity/costs of their research, they suggested that “while
offering preparation against future emerging viruses, this approach must be
considered in the context of the US government-mandated pause on Gain
Of Function (GOF) studies” (which has since been lifted). They also
speculated that " review panels may deem similar studies too risky to pursue
as increased pathogenicity in mammalian models cannot be excluded." It is
certainly the case that this experiment created a chimeric virus with very
high infectivity potential targeted to the human upper respiratory tract. Yet a
surprising observation is that the paper states that this research consortium
has permission to continue this research. It appears that optimisation gain of
function work on this chimeric virus did continue. We deduce from paper
authorships that this was done in the Wuhan Institute of Virology.
4. In 2018, as discussed earlier, Dr Shi's close colleague Peng Zhou, with
others, investigated a coronavirus outbreak associated with a fatal Swine
Acute Diarrhoea Syndrome (SADS) in Guangdong Province. This paper
relates that piglets had a tissue specific infection site located in the intestine
and that verification of the Bat Covid nature of this new SADS as the
disease-causing agent was confirmed. 25,000 piglets died. However, the
really interesting part of this study reports that in order to identify the
receptor(s) used by the SADS CoV, known coronavirus host cell receptors
were investigated: Angiotensin Converting Enzyme 2 (ACE2), Amino
Peptidase N (APN), and Di- Peptidyl Peptidase 4 (DPP4). None of these
receptors worked. But indirectly in their paper, the authors revealed their
ability to express and to test new receptors in the ways posited earlier.
Recollect that the model to do this was proven and reported in the 2010
work. Thus it is plain that SADS is a CoV infection utilising new tissue-
specific binding domains; but the authors provide no hint about which
receptor the virus is using in piglets except that it is not any of the best
known three. We have offered our deduction above. Pigs, of course, have
immune systems very similar to humans.
Now recollect that Menachery V.D et al in 2015 had shown that their
chimeric virus SHC014-MA15 could, against their prediction, very
successfully infect primary human upper airway epithelial cells (HAE) from
the cell-line 2B4 Calu-3. With this in mind, we next observed that in the
Covid-19 pandemic, a well-reported symptom in the early phase of the
infection is loss of taste, headache and a sore throat. We have discussed
this issue in the QRBD article in detail. But to summarise: in 2015 in a
research review (Workman et al, 2015) discussed bitter/sweet taste
receptors and the role these receptors play in mediating airway immune
functions. They concluded thus: "Over the past several years, taste
receptors have emerged as key players in the regulation of innate immune
defenses in the mammalian respiratory tract. Several cell types in the airway,
including ciliated epithelial cells, solitary chemosensory cells, and bronchial
smooth muscle cells, all display chemoresponsive properties that utilize
taste receptors."
Therefore we hypothesise the reconstructed historical aetiology of the Spike
as follows:
In 2008, Dr Zheng-Li Si and WIV colleagues successfully demonstrated
technical capabilities to interchange RBD’s between bat SARS-like and
human SARS viruses. Building upon this, the 2010 work (Hou et al, 2010)
perfected the ability to express receptors on human cells. On these
foundations, the central Gain of Function work that underpins the
functionalities of SARS-CoV-2 took place, carrying the WIV spike and
plasmid materials to bond successfully to a UNC Chapel Hill human
epithelial cell-line. This work (Menachery et al) produced a highly infectious
chimeric virus optimised to the human upper respiratory tract. In convergent
support of this hypothesis, both Lu (Lu et al, 2020) and Jia (Jia et al, 2020)
have now, in January and April 2020, shown that SARS-CoV-2 has a bat
SARS-like backbone but is carrying an RBD from a human SARS and Zhan et
al have, like us, noted unusual adaption to humans from the first isolate. In
the 2015 Chapel Hill work it was only ACE2 receptors that were discussed.
However, in 2018 Zhou P. et al demonstrated capabilities to clone other
6 receptors like APN and DPP4 and to test and compare these against the
(intestine) tissue specific SADS-CoV identified. Then, in the 2019-20 Covid-
19 pandemic, profuse symptoms indicating compromise of the bitter/sweet
receptors are reported. Taken all together, this implies that by employing
insights gained after 2015, as just deduced, a further optimization of the
2015 chimeric virus for additional binding to receptors/co-receptors such as
bitter/sweet specific upper airway epithelia receptors occurred. That would
help to explain the otherwise puzzling high infectivity and pathology
associated with SARS-CoV-2 and hence also help to explain the social
epidemiology of its spread.
Conclusion
We have deduced the internal logic of published research which resulted in
the exact functionalities of SARS-CoV-2, including the convergence of
agreement from difference classes of source, the timings of the stages of
the research and the development of documented capabilities by named
institutions and individuals. These meet the criteria of means, timing, agent
and place in this reconstructed historical aetiology to produce sufficient
confidence in the account to reverse the burden of proof. Henceforth, those
who would maintain that the Covid-19 pandemic arose from zoonotic
transfer need to explain precisely why this more parsimonious account is
wrong before asserting that their evidence is persuasive, most especially
when, as we have indicated, we note puzzling errors in their use of
evidence. In our companion article, in a similar forensic manner we will
explore the primary evidence used to sustain the hypothesis of zoonotic
transfer. In neither this article nor the next do we speculate about motive.
Oslo & London 1 July 2020
References:
Alan D. Workman, James N. Palmer, Nithin D. Adappa and Noam A. Cohen.
"The Role of Bitter and Sweet Taste Receptors in Upper Airway Immunity "
Curr Allergy Asthma Rep. 2015 December ; 15(12): 72. doi:10.1007/s11882-
015-0571-8.
Andersen, K. G., Rambaut, A., Lipkin, W.I., Holms, E. C., Garry, R. F., 2020,
"The proximal origin of SARS-CoV-2". Nat Med.
https://doi.org/10.1038/s41591-020-0820-9
Callaway E, "The Race for Coronavirus Vaccines", Nature, Vol 580, 30 April
2020, pp 576-7 (https://www.nature.com/articles/d41586-020-01221-y)
Hou Y, Peng C, Yu M, Li Y, Han Z, Li F, Wang LF, Shi Z., 2010, "Angiotensin-
converting enzyme 2 (ACE2) proteins of different bat species confer
variable susceptibility to SARS-CoV entry", Arch Virol, 155:1563–1569, doi:
10.1007/s00705-010-0729- 6Hou 2010
Thomas-Oliver Kleen, Alicia A Galdon, Andrew S Macdonald and Angus G
Dalgleish, Mitigating dysfunctional immunity in COVID-19: Trained Immunity,
BCG and ‘new old friends’, 2020. (paper submitted)
Lin Xu, Fuqiang Zhang, Weihong Yang, Tinglei Jiang, Guanjun Lu, Biao He,
Xingyu Li, Tingsong Hu, Gang Chen, Yun Feng, Yuzhen Zhang, Quanshui
Fan, Jiang Feng, Hailin Zhang & Changchun Tu, 2016, "Detection and
characterization of diverse alpha- and betacoronaviruses from bats in
China", Virologica Sinica, 31 (1): 69–77, doi: 10.1007/s12250-016-3727-3
Marzi A, Gramberg T, Simmons G, Möller P, Rennekamp AJ, Krumbiegel M,
Geier M, Eisemann J, Turza N, Saunier
B, Steinkasserer A, Becker S, Bates P, Hofmann H, Pöhlmann S, (2004) "DC-
SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the
S Protein of Severe Acute Respiratory Syndrome Coronavirus", Journal of
Virology, DOI: 10.1128/JVI.78.21.12090-12095.
Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu,
Wenling Wang, Hao Song, Baoying Huang, Na Zhu, Yuhai Bi, Xuejun Ma,
Faxian Zhan, Liang Wang, Tao Hu, Hong Zhou, Zhenhong Hu, Weimin Zhou,
Li Zhao, Jing Chen, Yao Meng, Ji Wang, Yang Lin, Jianying Yuan, Zhihao Xie,
Jinmin Ma, William J Liu, Dayan Wang, Wenbo Xu, Edward C Holmes,
George F Gao, Guizhen Wu, Weijun Chen, Weifeng Shi, Wenjie Tan.
“Genomic characterisation and epidemiology of 2019 novel coronavirus:
implications for virus origins and receptor binding”. Lancet 2020; 395: 565–
74. https://doi.org/10.1016/ S0140-6736(20)30251-8
7
Sørensen, B., Susrud, A., & Dalgleish, A. (2020). "Biovacc-19: A Candidate
Vaccine for Covid-19 (SARS-CoV-2) Developed from Analysis of its General
Method of Action for Infectivity". QRB Discovery, 1-17.
doi:10.1017/qrd.2020.8
Timothy Sheahan, Barry Rockx, Eric Donaldson, Amy Sims, Raymond
Pickles, Davide Corti, Ralph Baric, 2008, “Mechanisms of Zoonotic Severe
Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human
Airway Epithelium”. J Virol. https://doi.org/10.1128/JVI.02041-07
Vineet D Menachery, Boyd L Yount Jr, Kari Debbink, Sudhakar Agnihothram,
Lisa E Gralinski, Jessica A Plante, Rachel L Graham, Trevor Scobey, Xing-Yi
Ge, Eric F Donaldson, Scott H Randell, Antonio Lanzavecchia, Wayne A
Marasco, Zhengli-Li Shi & Ralph S Baric , 2015," A SARS-like cluster of
circulating bat coronaviruses shows potential for human emergence", Nature
Medicine, 21(12): 1508–1513. doi:10.1038/nm.3985
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D, (2020)
“Structure, Function, and Antigenicity of the SARS- CoV-2 Spike
Glycoprotein”, Cell, Volume 181, Issue 2, 16 April, Pages 281-292.e6, DOI:
https://doi.org/10.1016/j.cell.2020.02.058
Wan Y, Shang J, Graham R, Baric RS, Li F. 2020. "Receptor recognition by
the novel coronavirus from Wuhan: an analysis based on decade-long
structural studies of SARS coronavirus". J Virol 94: e00127-20.
https://doi.org/10.1128/JVI.00127-20.
Wuze Ren, Xiuxia Qu, Wendong Li, Zhenggang Han, Meng Yu, Peng Zhou,
Shu-Yi Zhang, Lin-Fa Wang, Hongkui Deng and Zhengli Shi, 2008,
“Difference in Receptor Usage between Severe Acute Respiratory Syndrome
(SARS) Coronavirus and SARS-Like Coronavirus of Bat Origin”. J Virol.
https://doi.org/10.1128/JVI.01085-07
Xian-Dan Lin, Wen Wanga, Zong-Yu Hao, Zhao-Xiao Wang, Wen-Ping Guo,
Xiao-Qing Guan, Miao-Ruo Wang, Hong-Wei Wang, Run-Hong Zhou, Ming-
Hui Li, Guang-Peng Tang, Jun Wu, Edward C. Holmes, Yong-Zhen Zhang,
2017, "Extensive diversity of coronaviruses in bats from China", Virology 507,
1–10, https://doi.org/10.1016/j.virol.2017.03.019
Yong Jia, Gangxu Shen, Yujuan Zhang, Keng-Shiang Huang, Hsing-Ying Ho,
Wei-Shio Hor, Chih-Hui Yang, Chengdao Li, Wei- Lung Wang. “Analysis of
the mutation dynamics of SARS-CoV-2 reveals the spread history and
emergence of RBD mutant with lower ACE2 binding affinity”. bioRxiv April
11,2020. https://doi.org/10.1101/2020.04.09.034942
Zhan S.H. et.al. (2020) "SARS-CoV-2 is well adapted for humans. What
does this mean for re-emergence"- bioRxiv
Zhou P, Fan H, Lan T, Yang XL, Shi WF, Zhang W, Zhu Y, Zhang YW, Xie QM,
Mani S, Zheng XS, Li B, Li JM, Guo H, Pei GQ, An XP, Chen JW, Zhou L, Mai
KJ, Wu ZX, Li D, Anderson DE, Zhang LB, Li SY, Mi ZQ, He TT, Cong F, Guo
PJ, Huang R, Luo Y, Liu XL, Chen J, Huang Y, Sun Q, Zhang XLL, Wang YY,
Xing SZ, Chen YS, Sun Y, Li J, Daszak P, Wang LF, Shi ZL, Tong YG & Ma JY,
(2018) "Fatal swine acute diarrhoea syndrome caused by an HKU2-related
coronavirus of bat origin", Nature 556, 255–258,
https://doi.org/10.1038/s41586-018-0010-9
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B,
Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen
XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX,
Wang YY, Xiao GF & Shi ZL, (2020) "A pneumonia outbreak associated with
a new coronavirus of probable bat origin", Nature 579, 270–273,
https://doi.org/10.1038/s41586-020-2012-7
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