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Yuri Deigin

@ydeigin

Aug 27

1/ A key weakness of the Huanan market zoonosis hypothesis is that all 16 earliest Wuhan patients with link to the market had lineage B of SARS2 which is phylogenetically placed later in the ancestry tree than lineage A.

2/ Lineage A initially represented 33% of the Wuhan early cases but quickly went extinct as lineage B seemed to have a fitness/growth advantage as evidenced by early epidemiological data.

3/ So lineage A is two mutations closer to ancestral bat viruses than lineage B and most likely lineage B evolved from it before eventually outcompeting it into oblivion. However, lineage A itself is not at the root of the SARS2 ancestry tree because several phylogenetically earlier genomes are known, i.e. ones that have even fewer mutations than lineage A when compared to bat viruses like RaTG13 or BANAL-52.

One such mutation is C18060T (i.e. bat viruses have a T nucleotide in their genomes [actually, a U as they are RNA viruses but let’s speak DNA here] in position 18060, while the reference human SARS2 genome, Wuhan-Hu-1, has a C nucleotide), and several investigators of SARS2 phylogeny (e.g. @jbloom_lab or Kumar et al. 2021) think that it is likely that the earliest ancestor of all human SARS2 viruses had that mutation.

Such an ancestor is sometimes called proCoV2, and it is basically lineage A with the C18060T mutation (so, in total, it is 3 mutations away from Huanan market’s lineage B: C8782T, C18060T, and T28144C).

Here is the Kumar et al. paper:

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Yuri Deigin

@ydeigin

Aug 24

1/

Besides the furin cleavage site (FCS), SARS2 has another unique feature mentioned in DEFUSE not yet seen in any natural SARS-like viruses – an ablated N-linked glycan at position N370. This glycan was ablated via a T372A amino acid mutation that came about via a double nucleotide mutation of the original ACT codon into GCA (the latter, incidentally, is the same codon as the one coding for alanine – out of 4 possible alanine codons – in the PRRA insertion which has created an FCS in SARS2).

Importantly, the T327A mutation greatly increases SARS2 infectivity in human lung cells but, just like an FCS, this kind of a mutation seems to have selective pressure AGAINST it in ancestral bat viruses.

DEFUSE’s interest in N-linked glycans stems from a very curious observation about SARS1 whose bat progenitor seems to have temporarily lost two of its N-linked glycans in civet SARS1 progenitors before re-acquiring them, and this led virologists to hypothesize that those glycans could be relevant for host switching. This is described in DEFUSE in a somewhat convoluted way:

“N-linked glycosylation: Some glycosylation events regulate SARS-CoV particle binding DC-SIGN/L-SIGN, alternative receptors for SARS-CoV entry into macrophages or monocytes [76,77]. Mutations that introduced two new N-linked glycosylation sites may have been involved in the emergence of human SARS-CoV from civet and raccoon dogs [77]. While the sites are absent from civet and raccoon dog strains and clade 2 SARSr-CoV, they are present in WIV1, WIV16 and SHC014, supporting a potential role for these sites in host jumping. To evaluate this, we will sequentially introduce clade 2 disrupting residues of SARS-CoV and SHC014 and evaluate virus growth in Vero cells, nonpermissive cells ectopically expressing DC-SIGN, and in human monocytes and macrophages anticipating reduced virus growth efficiency. We will introduce the clade I mutations that result in N-linked glycosylation in rs4237 RBD deletion repaired strains, evaluating virus growth efficiency in HAE, Vero cells, or nonpermissive cells +/- ectopic DC-SIGN expression [77]. In vivo, we will evaluate pathogenesis in transgenic hACE2 mice.”

The [77] paper cited in DEFUSE is a 2007 work by Han et al. titled “Specific Asparagine-Linked Glycosylation Sites Are Critical for DC-SIGN- and L-SIGN-Mediated Severe Acute Respiratory Syndrome Coronavirus Entry”. It looked at the 5 civet progenitor strains of SARS1 and showed that initially those strains did not have glycans around positions N227 and N699 but then eventually acquired them in civet progenitors and kept in human SARS1.

2/

What the 2007 paper did not know at the time that the DEFUSE authors pointed out is that the bat progenitor strains like WIV1/Rs3367 or SHC014 also have glycans at those positions. This is what likely made the DEFUSE authors interested in the host jumping potential of these glycans and potentially genetically modifying them to further study their role:

3/ Circling back to the DEFUSE proposal, the N370 glycan in SARS2 is the same glycan as N357 in SARS1 which was implicated as being important for DC-SIGN binding in 2006:

ncbi.nlm.nih.gov/pmc/articles/P…

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Yuri Deigin

@ydeigin

Jun 20

🧵Ben Hu being named as one of the 3 WIV staffers sick with Covid-like symptoms in Oct/Nov 2019 is an interesting 🧩 to the Covid origins saga. He connects several threads together: DEFUSE, WIV sampling in Mengla County (which borders Laos), RmYN02 with its proto-FCS etc. -->

He even has a possible connection to the mysterious pre-pandemic pangolin coronavirus (that has a near-identical RBD to SARS2) reported in mid-2019 by Guandong’s GIABR.

To recap, the latest leak added explosive details about 3 WIV staffers having Covid-like symptoms (loss of smell/taste & pneumonia w/ ground glass opacities) in Fall 2019—the details being that the 3 staffers were CoV experts from Zhengli Shi’s lab (Ben Hu, Yu Ping, and Yan Zhu).

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Yuri Deigin

@ydeigin

Apr 5

@samhusseini

Ok, the 2014 West African Ebola outbreak is also looking suspicious. Until 2014, the outbreaks of that (Zaire) Ebola species were confined to Central Africa, over 5000 km away.

Here’s a detailed article about that outbreak by @samhusseini and @BioSRP.

independentsciencenews.org/health/did-wes…

twitter.com/i/web/status/1…

One aspect of the story I found interesting is that while some virologists like Bob Garry have denied that the Kenema lab (rumored to have possibly caused the Ebola outbreak in West Africa) was studying Ebola before the outbreak, I found the following study which reported… twitter.com/i/web/status/1…

twitter.com/i/web/status/1…

Btw to seed their cell culture virus propagation experiments, the above researchers used a Kikwit strain of the Zaire Ebola previously sampled during a 1995 outbreak in Central Africa. Here is where the Makona strain of the 2014 West African outbreak is placed on the phylogenetic… twitter.com/i/web/status/1…

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Yuri Deigin

@ydeigin

Mar 6

1/n
The Wuhan CDC is back in focus after reports that it was the reason behind DOE changing its Covid origin assessment to a possible lab leak. Really curious what data led to that conclusion, hope they'll declassify it! For now, let me share some observations about Wuhan CDC:

2/n
WHCDC was, of course, an early lab leak suspect, as outlined in a Feb 2020 preprint by Xiao & Xiao where they pointed to Junhua Tian (JHT)’s interest in bat ticks, as well as his statements about having to quarantine after being attacked by bats:
web.archive.org/web/2020021414…

3/n
In 2021 WaPo wrote an interesting profile of Junhua Tian:

“Tian is by title an associate chief technician in the Wuhan CDC’s pest-control department, but he has a reputation as a swaggering adventurer in his work with bats and insects."

washingtonpost.com/world/asia_pac…

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Yuri Deigin

@ydeigin

Mar 4

https://twitter.com/ydeigin/status/1631785943916060672

At the protein level the BANAL-52 spike is ~99% identical to the pre-FCS SARS2 spike, and its RBD (responsible for binding to the ACE2 receptor) differs by just 1 aa. Other BANAL genes are 98-99% identical to SARS2. So BANAL-52+FCS itself would do quite well at human spillover.

https://twitter.com/ydeigin/status/1631785943916060672

Of course a lab in Wuhan could have had a BANAL-like bat strain even closer to SARS2 than strains found in Laos in 2020. The point is, all it takes for a BANAL-like virus to become human-transmissible is an FCS, as it opens up respiratory tropism. Some papers:

researchsquare.com/article/rs-180…

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