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Discussion: Chinese Academy of Sciences (CAS) in Wuhan has been working with bats and coronavirus for many years - DNA manipulations, cloning....

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    SOCIETY
    Posted today at 10:21
    ANALYSIS

    Origins of Covid-19: the trail of a leak from the Wuhan laboratory relaunched, China at bay

    Pierre-Antoine Donnet

    A serious lead is emerging on the origin of Covid-19. The coronavirus could well come from bats that infected workers in a mine in Yunnan in southwest China in 2012. Samples of the virus were reportedly taken by the Wuhan Institute of Virology, relaunching the hypothesis of the accidental leak at the origin of the pandemic. At the same time, calls are becoming increasingly urgent across the world to China, called on from all sides to finally shed light on a pandemic that has killed more than 2.6 million people until present.

    Remember, a little over a year ago, these images of sick pangolins, wild animals sold on the stalls of the Wuhan wet market, a few stray bats. A scenario that has long masked the true origin of the virus. To launch the counter-attack, Beijing propaganda had come to accuse the US military of being responsible for the contamination in Wuhan during the World Military Games held in the city in October 2019. At the beginning of last September, Chinese official media had even posted on social networks a video evoking "200 mysterious biosafety laboratories set up by the American army all around the world",likely to have released the new coronavirus. Then she had moved on to an equally improbable thesis of frozen products imported from abroad.

    The reality is, of course, to be sought elsewhere. One lead is becoming more and more credible, but one that the Chinese authorities are seeking by all means to hush up: that of the contamination of workers in 2012 in a mine in Yunnan which would then have circulated quietly until a A prominent Chinese researcher does not bring the virus back to the P4 laboratory of the Wuhan Institute of Virology. Was there an accident and the virus escaped from the lab?

    This is one of the key questions raised, in an open letter dated March 4, a group of 26 international scientists. They denounce the lack of access offered to WHO investigators in Wuhan at the beginning of the year and recommend not to rule out the trail of an accidental leak. According to the signatories of the letter, it would be necessary to be able to examine the different scenarios, in particular one where an employee of the laboratory in Wuhan could have been accidentally infected while taking samples of coronavirus, during the transport of sick animals or during the handling of waste from of this type of sampling.

    CULTURE OF SILENCE

    Let's take a closer look at this trail leading from Yunnan to the Wuhan Institute of Virology. A well-documented article published on December 22 by Le Monde explains the sequence. On April 25, 2012, a 42-year-old man was admitted to hospital in Kunming, the provincial capital of Yunnan, some 1,500 km southwest of Wuhan. He has been subject to a persistent cough for two weeks, suffers from a high fever and especially from worsening respiratory distress. The next day, three other patients, aged 32 to 63, with similar symptoms, were admitted to the same establishment. Two days later, a 45-year-old man was in turn hospitalized there. A sixth, 30, joined them a week later.

    All share more or less the same symptoms of severe pneumonia. Their chest scans indicate bilateral involvement of the lungs, with ground glass opacities, which are today recognized as relatively characteristic of Covid-19, although not specific. Three of them show signs of thrombosis, an obstruction of the vessels again quite typical of complications from the new coronavirus.

    All of them have in common that they worked in an abandoned mine in Tongguan, in Mojiang County. A mine populated by several colonies of horseshoe bats - known as "horseshoe bats" - where the six men spent up to two weeks in the galleries of the guano of flying mammals. Three of them died in hospital, after twelve, forty-eight and one hundred and nine days of hospitalization, respectively. The two youngest escaped after a stay of less than a week, while another, aged 46, would not be discharged from Kunming hospital until four months after his admission.

    However, the Wuhan Institute of Virology collected samples from this Yunnan coronavirus in 2012. Information confirmed by the management of the laboratory in an article published by the journal Nature on November 17.. What has happened since? Beijing is keeping the most absolute silence on this trail and the mine in question is now hermetically sealed, carefully kept out of prying eyes. The culture of silence and concealment of the Chinese government once again brought to light, but this time on a global subject. Teams of foreign journalists were ruthlessly chased away by angry villagers as cameras were installed at the entrance to the mine and roadblocks blocked all access to the site.

    "85% CHANCE"

    The mission of experts from the World Health Organization (WHO) to Wuhan to try to determine the origin of the virus last February ended in a complete fiasco. Not only had the Chinese authorities negotiated step by step the terms of the investigation with the WHO to the detriment of the independence of the expertise, not only the experts, certainly reputed, had all been co-opted by Beijing but, according to an investigation of the New York Times, their work had to be content with work already carried out under the aegis of Beijing.

    The road traveled has been immense over the past year. At the very beginning of the epidemic, any mention of the lab trail was categorized as pure conspiracy theory, or associated with the anti-Chinese attacks by Trump and his administration. However, this hypothesis did not actually come from the camp of the former Republican president, as J?r?my Andr?, correspondent for Le Point in Hong Kong , explained . Jamie Metzl, a researcher at the Atlantic Council, an American think tank , former member of Joe Biden's cabinet in the Senate and former adviser to the Clinton administration, was the first in Washington to argue that a research accident could have lead to the catastrophic pandemic of 2020.

    This figure close to the Democratic establishment exposed, as early as April 2020, the numerous arguments and evidence leading him to conclude that there is "an 85% chance that the pandemic started with an accidental leak". It is precisely Jamie Metzl who coordinated the open letter of the 26 scientists published on March 4. An opinion that weighs, coming from a specialist in public health and research in genetic engineering, a familiar with China, and an expert less suspicious of wanting to politicize the file than Donald Trump or Mike Pompeo.

    On March 11, Chinese Premier Li Keqiang promised that China would continue to cooperate with the WHO to continue researching the origin of the virus with them. "We will continue to work with the WHO to take this work further," he said. Hundreds of scientists around the world have joined in to take China at its word. Its credibility depends on it.
    The famous Chinese sculptor and director Ai Weiwei, who now lives in Portugal, shot a film, Coronation, on the epidemic in Wuhan , directing twelve amateur videographers from a distance. According to the artist, ?the world will probably never know what really happened in Wuhan. [?] The communist regime is very powerful and for it, keeping this secret is a priority. "

    Une piste sérieuse est en train d'émerger sur l'origine du Covid-19. Le coronavirus pourrait bien provenir de chauve-souris ayant contaminé des ouvriers dans une mine du Yunnan au sud-ouest de la Chine en 2012. Des échantillons du virus auraient été prélevés par l'Institut de virologie de Wuhan, relançant l'hypothèse de la fuite accidentelle à l'origine de la pandémie. Dans le même temps, les appels se font de plus en plus pressants à travers le monde en direction de la Chine, sommée de toutes parts de faire enfin la lumière sur une pandémie qui a tué plus de 2,6 millions de personnes jusqu'à présent.

    "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
    -Nelson Mandela

    Comment


    • In 2018, Diplomats Warned of Risky Coronavirus Experiments in a Wuhan Lab. No One Listened.

      After seeing a risky lab, they wrote a cable warning to Washington. But it was ignored.

      03/08/2021 04:30 AM EST
      By JOSH ROGIN

      ...The statement said the U.S. intelligence community had evidence that several researchers at the Wuhan Institute of Virology laboratory were sick with Covid-like symptoms in autumn 2019?implying the Chinese government had hidden crucial information about the outbreak for months?and that the WIV lab, despite ?presenting itself as a civilian institution,? was conducting secret research projects with the Chinese military. The State Department alleged a Chinese government cover-up and asserted that ?Beijing continues today to withhold vital information that scientists need to protect the world from this deadly virus, and the next one.?

      ... To some inside the government, the name of the laboratory was familiar. Its research on bat viruses had already drawn the attention of U.S. diplomats and officials at the Beijing Embassy in late 2017, prompting them to alert Washington that the lab?s own scientists had reported ?a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory.?

      But their cables to Washington were ignored.

      more...

      https://www.politico.com/news/magazi...excerpt-474322
      Last edited by sharon sanders; March 15, 2021, 04:51 PM. Reason: shortened due to copyright concerns

      Comment



      • Lab Leak: A Scientific Debate Mired in Politics ? and Unresolved

        More than a year into the SARS-CoV-2 pandemic, some scientists say the possibility of a lab leak never got a fair look.

        BY CHARLES SCHMIDT
        03.17.2021
        ...
        After Chinese scientists posted a draft genome of the novel coronavirus SARS-CoV-2, the disease culprit in Wuhan, Petrovksy ? who by this time had put skiing on the backburner to work from his Colorado home office ? directed his colleagues down under to run computer modeling studies of the viral sequence, a first step towards designing a vaccine.

        This generated a startling result: The spike proteins studding SARS-CoV-2 bound more tightly to their human cell receptor, a protein called ACE2, than target receptors on any other species evaluated. In other words, SARS-CoV-2 was surprisingly well adapted to its human prey, which is unusual for a newly emerging pathogen. ?Holy ****, that?s really weird,?? Petrovsky recalls thinking.
        ...
        David Relman, a microbiologist at Stanford University, says a lab leak was never the subject of a ?fair and dispassionate discussion of the facts as we know them.? Instead, tempers soon began to flare as those calling for a closer look at possible lab origins were dismissed as conspiracy theorists spouting misinformation.
        ...
        Perhaps no one played a greater role in galvanizing scientific opinions in support of natural origins than Peter Daszak, president of EcoHealth Alliance, a New York-based environmental health nonprofit. A long-time Wuhan Institute of Virology collaborator, Daszak ? who in what many sources described as a conflict of interest was a member of the WHO-led team that visited China earlier this year ...Daszak is purported to have written a first draft of the Lancet statement condemning hypotheses other than natural origins as conspiracy theories. After repeated requests for an interview, the EcoHealth Alliance and Daszak declined to comment for this story.
        ...
        WHEN ASKED WHY he thought Daszak and others pushed so strongly against the possibility of a lab leak, Relman says they may have wanted to deflect perceptions of their work as endangering humankind. With so-called ?gain-of-function? experiments, for instance, scientists genetically manipulate viruses to probe their evolution ? sometimes in ways that boost virulence or transmissibility
        ...
        In Australia, Petrovksy says he is trying to stay above the fray. He says he was warned to avoid speaking publicly about his modeling findings. ?A lot of people advised us ?even if it?s good science, don?t talk about it. It will have a negative impact on your vaccine development. You will get attacked; they will try to discredit you.?? But in the end, that?s not what happened, says Petrovsky. Last year, amid the origins debate, his team became the first in the Southern Hemisphere to take a vaccine for Covid-19 into human clinical trials.

        ?If we are at the point where all science is politicized and no one cares about truth and only being politically correct,? he says, ?we may as well give up and shut down and stop doing science.?

        More than a year into the SARS-CoV-2 pandemic, some scientists say the possibility of a lab leak never got a fair look.
        "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
        -Nelson Mandela

        Comment


        • Emily
          Emily commented
          Editing a comment
          Very good article.

      • evryone (except me ;-)) who is discussing this seems to be biased. Searching for evidence that supports his/her predefined (political)
        position while ignoring the counter-evidence.
        agenda driven science , not curiosity driven science, I saw that 2002-2003 WMDs, 2006-2007 H5N1 , 2011-2012 "Birthers",
        2014 MH17

        there are only 2 nucleotides differences in SARS2 and RmYN02 in the area 12825-14033 suggesting recent recombination.
        I don't see this argument being discussed ?!
        I'm interested in expert panflu damage estimates
        my current links: http://bit.ly/hFI7H ILI-charts: http://bit.ly/CcRgT

        Comment


        • Emily
          Emily commented
          Editing a comment
          Is that discussed here, gsgs?
          The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infec ...


          There are some interesting comments. I got the sense that recombination was dismissed early on. I don't know why but maybe because it could happen in a lab, too, via GOF. (That is what the first comment addresses.)

        • gsgs
          gsgs commented
          Editing a comment
          no, I mean a possible smaller, recombination, not the spike. Some evidence for a recent
          common anchester in that area. In a low mutation area, though. But I didn't see
          this in other bat-viruses.
          Meanwhile we also got PrC31 with some other close areas with other sarbeco.
          But the 2 nucleotides in >1000 positions remains top.

      • Exclusive: Lead Chinese scientist of WHO joint team addresses key issues ahead of joint report release

        Liang Wannian speaks to GT on delayed release of joint report, sharing of early patient data, and ruling out lab leak

        By Chen Qingqing, Cao Siqi, Zhao Yusha and Bai Yunyi
        Published: Mar 17, 2021 09:50 PM
        ...

        Lab leak? Experts agree on no further origin studies on the hypothesis of 'lab leak'

        GT: At the press conference held by the joint experts team on February 9, they said it is "extremely unlikely" that the virus leaked from a lab in China. But WHO director-general Tedros Adhanom Ghebreyesus said that all hypotheses are still open in the probe into the coronavirus origins, and require further analysis and study. The statement is seen as the lab theory is not excluded. What's your opinion on this?

        Liang: There are various possibilities for the virus origin. During this joint study, our experts visited Hubei Provincial Center for Disease Control and Prevention, Wuhan Center for Disease Control and Prevention, Wuhan Institute of Virology and other institutes and bio-safety labs. They also had candid, deep communication with experts from those institutions. After their field visits and study, the experts team agreed unanimously that it is extremely unlikely that the virus leaked from the lab. So future virus origins-tracing missions will no longer be focused on this area, unless there is new evidence.

        The joint study is an independent scientific research mission, and its conclusion represents the result of the research the joint team conducted. We hope that all sides will uphold a scientific attitude and leave the origins-tracing work to professionals and scientists.
        ...


        ------------------------------------------------------------------------------------

        Note:
        The Global Times (simplified Chinese: ????; traditional Chinese: ????; pinyin: Hu?nqi? Sh?b?o) is a daily tabloid newspaper under the auspices of the Chinese Communist Party's flagship People's Daily newspaper, commenting on international issues from a nationalistic perspective.

        https://en.wikipedia.org/wiki/Global_Times
        "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
        -Nelson Mandela

        Comment


        • Pathfinder
          Pathfinder commented
          Editing a comment
          Peter Daszak@PeterDaszak retweeted the link to this article 4 times since yesterday.

      • Originally posted by Pathfinder View Post
        Coronavirus: WHO 'not invited' to join China's COVID-19 investigations
        ...
        Tom Cheshire
        Asia correspondent @chesh

        Friday 1 May 2020 04:53, UK

        China has refused repeated requests by the World Health Organisation to take part in investigations into the origins of COVID-19, the WHO representative in China has told Sky News.
        ...
        "WHO is making requests of the health commission and of the authorities," he said. "The origins of virus are very important, the animal-human interface is extremely important and needs to be studied.

        "The priority is we need to know as much as possible to prevent the reoccurrence."
        ...
        Dr Galea also told Sky News that the WHO had not been able to investigate logs from the two laboratories working with viruses in Wuhan, the Wuhan Institute of Virology and the Wuhan CDC.

        "From all available evidence, WHO colleagues in our three-level system are convinced that the origins are in Wuhan and that it is a naturally occurring, not a manufactured, virus," he said.

        Nevertheless, according to Dr Galea, the laboratory logs "would need to be part of any full report, any full look at the story of the origins".

        ...
        https://news.sky.com/story/coronavir...tions-11981193

        9 months later...


        Bloom Lab
        @jbloom_lab
        ?
        18h
        So regardless of opinion on plausibility of natural origins vs lab escape, all scientists should agree there needs to be full sharing of sequences of SARS-related viruses studied in Wuhan, including from Mojiang mines where closest known relative of #SARSCoV2 was found. (7/9)
        Bloom Lab
        @jbloom_lab
        ?
        18h
        That?s the first step towards enabling an objective scientific discussion. (8/9)
        Bloom Lab
        @jbloom_lab
        Replying to
        @jbloom_lab
        And that's why I was disappointed to hear
        @PeterDaszak
        say WHO team didn't even *ask* Wuhan Institute of Virology to see database of virus sequences because *he* knows it doesn't have anything relevant
        (https://twitter.com/McWLuke/status/1369686004924309504). Science is sharing data, not assertions. (9/9)
        ------------------------------------------

        See the video here:

        ?????? Luke
        @McWLuke
        Here's the moment
        @PeterDaszak
        confirms he DID NOT ask for the data from the MISSING BAT VIRUS DATABASE.



        10:26 AM ? Mar 10, 2021

        "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
        -Nelson Mandela

        Comment


        • 2017 INDEPENDENT SCIENCE NEWS - GOOD WITH SCIENCE. ISSN 2374-3123 Part of the Bioscience Resource Project
          Except where otherwise noted, content on this site is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.



          Why China and the WHO Will Never Find a Zoonotic Origin For the COVID-19 Pandemic Virus

          independentsciencenews.org/commentaries/why-china-and-the-who-will-never-find-a-zoonotic-origin-for-the-covid19-pandemic-virus/

          February 16, 2021 by Jonathan Latham, PhD and Allison Wilson, PhD

          In China there is a popular joke about the southern city of Guangzhou (Canton). A visiting space alien, curious to learn about Chinese customs, tours its various provinces. Arriving in Guangzhou the alien asks the locals what their interests are. The Cantonese oblige their guest by putting the alien in a soup pot and eating it. This joke hinges on the Cantonese fondness for cooking with unusual species, many obtained from far away.
          This feature of Canton?s cuisine was implicated in the original SARS (Severe Acquired Respiratory Syndrome) pandemic of 2002-04, which began in Guangzhou. It is thought that the virus arrived there with palm civets imported for speciality dishes (Wang et al., 2005).
          But this culinary connection also marks a defining difference between the first SARS coronavirus pandemic and the current one. The COVID-19 (SARS-CoV-2) pandemic began in Wuhan, but Wuhan was considered a comparatively unlikely location for a natural (zoonotic) coronavirus spillover (Yu et al., 2019). It has no cultural or geographic or climatic predisposing factors.
          For example, being fairly far north, bats are not abundant in Wuhan and Hubei province has few bat coronaviruses compared to hotspots like Yunnan and Guangdong (Yu et al., 2019). Unlike Canton, Wuhan is not famous for exotic fare. Nor is Wuhan near animal smuggling and trading origins (Li et al. 2019). It was for this reason that researchers from the Wuhan Institute of Virology (the WIV), which is the prime suspect in the various lab leak theories, mostly had to travel thousands of kilometres to find bats with coronaviruses (Yu et al., 2019). Furthermore, when WIV researchers needed to study a Chinese population that was not routinely exposed to bat coronaviruses (as a control group), they chose Wuhan residents (Wang et al. 2018; Li et al. 2019).
          It is consequently a mystery, if SARS-CoV-2 does have a zoonotic origin, why COVID-19 should have emerged where it did. As Zheng-li Shi, head of coronavirus research at the WIV told Scientific American, in March 2020: ?I had never expected this kind of thing to happen in Wuhan, in central China?.
          What is the probability of a natural zoonotic coronavirus outbreak starting in Wuhan?

          It is possible, and potentially helpful, to put numbers on Zheng-li Shi?s surprise. Numbers can more precisely show the incongruity of an outbreak occurring in Wuhan. But before using them it is important to specify the assumptions required so that these numbers can be treated with appropriate caution.
          Such a calculation requires that we set aside momentarily all the varied, potentially important, but hard-to-quantify-and-mostly-unknown local factors, like those mentioned above, that may make certain locations or populations less or more likely to originate a pandemic. (For a broader discussion of these factors see e.g. Graham et al., 2013).
          Given these provisos, and knowing that (1) bats and other animals which harbour coronaviruses are found practically all over the world, and (2) that the population of Wuhan is 11 million, and that (3) the global population is 7 billion, we can calculate the likelihood of Wuhan being the epicentre of a natural zoonotic coronavirus pandemic: The chance of a person from Wuhan being patient zero is approximately 1 in 630.
          Therefore, if we were Zheng-li Shi, we would have ?never expected? a natural zoonotic outbreak in Wuhan either. Imagine her surprise, and that of her colleagues when, in December 2019, they learned of a local coronavirus outbreak. They (and other researchers) travel all over the world, and not just China, looking for coronaviruses yet a pandemic breaks out in Wuhan, under their very noses. It truly is, very, very, unlikely that a natural zoonotic pandemic would start in Wuhan. Yet no commentator on the outbreak seems to have properly acknowledged the true scale of this improbability.
          The second coincidence is an evolutionary coincidence

          But there is, in fact, a second coincidence regarding the origin of the COVID19 pandemic. This coincidence has seemingly been entirely disregarded; but it too points strongly to a lab origin. The underlying logic is quite simple and it has to do with the evolution of coronaviruses.
          Zheng-li Shi?s laboratory at the WIV is a world centre of coronavirus research. This has been mentioned often and is widely known. In particular, the Wuhan Institute of Virology is a world-leading site for bat coronavirus collection (and the virus came from a bat). But what has not been foregrounded is that, even within the coronaviruses, Zheng-li Shi?s laboratory had, of the 28 relevant coronavirus species, singled out just one of them as their special focus. And it is a member of this species (called the ?SARS-related coronaviruses?) that broke out in Wuhan in 2019.
          This, then, is a further curious coincidence: for a pandemic coronavirus (SARS-CoV-2) to emerge in Wuhan and be a member of the species most studied at the Wuhan Institute of Virology.
          The logic of coronavirus pandemics

          A fuller appreciation of this coincidence requires visualising coronavirus evolution and understanding the research agenda at the WIV.
          The coronaviruses are divided into four types: Alpha-, Beta-, Gamma- and Delta- coronaviruses. These are shown in Fig. 1 which is a phylogenetic (evolutionary) tree adapted from a paper by Li et al., 2020. (The print is small and so here is a link to the original figure.)



          Fig. 1. WIV Phylogenetic Coincidence (Adapted from Li et al., 2020)Of this phylogenetic tree, only the Alpha (pink) and Beta (green) coronaviruses will be considered here. This is because the Gamma (yellow) and Delta (blue) coronaviruses are few, not known to infect humans, and therefore questionably relevant.
          As of February 2020, when Li et al. created this figure, there were 28 species of Alpha- and Betacoronaviruses. (Note: a species does not precisely equate to single tips on the phylogenetic tree in Fig 1. because some species have multiple members.)
          It is important to appreciate, however, that we have no reason to suppose that a pandemic coronavirus could not have emerged from any branch of this phylogenetic tree. Indeed, the last coronavirus to jump into humans (before 2019) was MERS (Middle East Respiratory Syndrome) in 2012. MERS is a Betacoronavirus and was an unknown species before it started infecting humans. See the green arrow in Figure 2. The original SARS virus was also unknown as a species at the time it emerged as a human pathogen in 2002.



          Fig. 2. WIV Phylogenetic Coincidence (Adapted from Li et al., 2020)This unpredictability is also apparent from Zheng-li Shi?s choice of ?disease X?. In 2018 the WHO announced a discussion list of pandemic priority diseases, which included Ebola, Rift Valley Fever, and other viruses. Alongside these known diseases the WHO asked experts to nominate a presently unknown candidate. Zheng-li Shi proposed that: ?Disease X could be a transmissible infectious disease caused by a novel coronavirus originated from bats? (Jiang and Shi 2020). In other words, she did not predict any more narrowly than that the next pandemic would be caused by an Alpha- or Betacoronavirus.
          The apparently random nature of coronavirus spillovers to humans is also apparent from inspection of Figure 3.



          Fig. 3. WIV Phylogenetic Coincidence (Adapted from Li et al., 2020)Figure 3 shows all of the six human coronaviruses identified prior to this pandemic. They are (from the top of the figure): HCoV-NL63, HCoV-229E, MERS, SARS, HCoV-OC43 and HCoV-HKU1. The six are each indicated in Figure 3 by green arrows, except for SARS, which is represented by a black arrow.
          What Figure 3 illustrates is that human coronaviruses are distributed widely across the coronavirus family tree. That is to say, previous spillovers to humans happened at diverse and seemingly random points on the coronavirus tree and have involved both Alpha- and Betacoronaviruses.
          The SARS-CoV-2 outbreak

          With these prior assumptions stated we can then ask the question: where on the tree would one have expected (prior to the COVID-19 pandemic) the next novel coronavirus to emerge?
          The answer is, if it were a natural or semi-natural spillover (i.e. a zoonosis)??from a random spot on the tree. It might have been an Alphacoronavirus or a Betacoronavirus. It might even, like MERS and SARS, be a novel species, since presumably there are still many undiscovered coronavirus species. The crucial point is that the chance of a spillover coming from each species is, as far as anyone knows, seemingly equal.
          So where, phylogenetically speaking, did SARS-CoV-2 emerge?
          The answer is shown in Figure 4 (below) in which the red arrow indicates the site of emergence of SARS-CoV-2.



          Fig. 4. WIV Phylogenetic Coincidence (Adapted from Li et al., 2020)It emerged from the same species as the original SARS, hence its name. As noted above, this particular species is known to taxonomists as the ?SARS-related coronaviruses? after its then most famous member (Coronavirus Study Group of the International Committee on Taxonomy of Viruses, 2020).
          As discussed, from a zoonotic perspective, nothing appears to be special about these SARS-related coronaviruses. Consequently, the emergence of a second pandemic virus from the same coronavirus species constitutes a second surprising coincidence. We can again calculate its probability. If each Alpha and Betacoronavirus species is equally likely to spill over to humans, which is consistent with our understanding, then the probability of a virus from the SARS-related coronavirus species starting a zoonotic pandemic is 1 in 28. (And if there are undiscovered coronavirus species??pretty much a certainty??the number will be greater still).
          It is a coincidence that, just like the emergence in Wuhan, heavily favours a lab escape if we take into account the specifics of the coronavirus research programme at the WIV, which are outlined below.
          China?s research on SARS-related coronaviruses

          Consider the following list of publication titles, many accepted in prestigious journals, from between 2005 and the start of the pandemic in late 2019. They are all authored by Zheng-li Shi. These eighteen research papers constitute the main focus of her published output. What they have in common is that all use the phrase ?SARS-like coronavirus? or, later, ?SARS-related coronavirus? or a close variant (all are bolded below). These phrases should be understood as technical terms. They denote viruses extremely closely related to SARS and only distantly related to other coronaviruses:
          1. ?Bats Are Natural Reservoirs of SARS-like Coronaviruses? (2005);
          2. ?Full-length genome sequences of two SARS-like coronaviruses in horseshoe bats and genetic variation analysis? (2006);
          3. ?Evidence of the recombinant origin of a bat severe acute respiratory syndrome (SARS)-like coronavirus and its implications on the direct ancestor of SARS coronavirus? (2008);
          4. ?Difference in Receptor Usage between Severe Acute Respiratory Syndrome (SARS) Coronavirus and SARS-Like Coronavirus of Bat Origin? (2008);
          5. ?Virus-like particles of SARS-like coronavirus formed by membrane proteins from different origins demonstrate stimulating activity in human dendritic cells? (2008);
          6. ?Immunogenicity difference between the SARS coronavirus and the bat SARS-like coronavirus spike (S) proteins? (2009);
          7. ?Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans? (2010);
          8. ?Immunogenicity of the spike glycoprotein of Bat SARS-like coronavirus? (2010);
          9. ?Bat severe acute respiratory syndrome-like coronavirus ORF3b homologues display different interferon antagonist activities? (2012);
          10. ?Identification of immunogenic determinants of the spike protein of SARS-like coronavirus? (2013);
          11. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor (2013);
          12. ?A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence? (2015);
          13. ?Bat severe acute respiratory syndrome-like coronavirus WIV1 encodes an extra accessory protein, ORFX, involved in modulation of the host immune response? (2016);
          14. Longitudinal surveillance of SARS-like coronaviruses in bats by quantitative real-time PCR? (2016);
          15. ?Cross-neutralization of SARS coronavirus-specific antibodies against bat SARS-like coronaviruses? (2017);
          16. ?Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus? (2017);
          17. ?Serological evidence of bat SARS-related coronavirus infection in humans, China? (2018);
          18. ?Geographical structure of bat SARS-related coronaviruses? (2019).
          What this list demonstrates is that, while Zheng-li Shi at the WIV focused on virus collection, above all, she dedicated her research to understanding zoonotic spillovers to humans of one species alone: the SARS-related coronaviruses.
          So while most discussions of a potential lab escape have mentioned that SARS-CoV-2 emerged within commuting distance of the WIV and that researchers at the WIV worked on bat coronaviruses, none have mentioned that the coincidence is much greater than that. Zheng-li Shi concentrated, especially with her potentially highly risky molecular research, on the particular species of coronavirus that is responsible for the pandemic.
          There is a simple reason for this focus. The original SARS outbreak in 2002-04 had a major impact in China. Finding the origin, explaining SARS and its symptoms, and preventing a repeat all became major research priorities for Chinese scientists.
          To be sure, Zheng-li Shi published papers on other coronavirus species over that same time-period, for example on MERS, and even some on non-coronaviruses; but these articles tended to be one-offs and co-authorships with other labs. The large majority of her output and the dominant theme of her research was collecting and manipulating SARS-related coronaviruses to determine the potential for human spillover.
          So, if one accepts as reasonable the assumptions made above, the probability of Wuhan being the site of a natural SARS-related coronavirus outbreak is obtained by multiplying 1 in 630 by 1 in 28. The chance of Wuhan hosting a SARS-related coronavirus outbreak is thus 17,640?1.
          The criticism will doubtless be made that the geographic and the phylogenetic evidence described here are circumstantial?mere coincidences. But critiquing evidence as circumstantial is based on a common logical misconception?that circumstantial evidence represents a special category of evidence. As the philosopher David Hume first argued, all evidence of causation is composed of coincidences. All an observer can do is to add up the coincidences until they surmise that the threshold of reasonable doubt has been surpassed. Conclusions are always provisional, but in the absence of evidence to the contrary, anyone open to persuasion ought at this point to conclude that a probability of 17,640?1 far exceeds that threshold. A lab escape should at this point be the default hypothesis.
          Such a conclusion is only reinforced by much of the important information that has emerged since the outbreak began. We now know, for example, that, at the time of the outbreak, Zheng-li Shi and her colleagues had in their freezers the virus sample known as RaTG13. Among all the known coronaviruses, including within the SARS-related coronaviruses, RaTG13 is by far the closest relative of SARS-CoV-2. We also know that Zheng-li Shi implied she had not actively studied RaTG13 prior to the outbreak (in Zhou et al, 2020). We now know this was false and they had been studying it since at least 2017 (Zhou et al. 2020 addendum). These facts again do not support a natural zoonotic origin.
          The lack of a zoonotic theory

          If there were a credible zoonotic origin theory for the emergence of SARS-CoV-2 then such a calculation might be considered moot. But, despite considerable academic discussion (e.g. Leitner and Kumar, 2020; Seyran et al. 2020; Sallard et al., 2020) and a WHO investigation, there is still no substantive zoonotic theory to speak of. Snakes, Bamboo rats, pangolins, mink, turtles, dogs, civets, whales, and frozen cod, have all, at various times, been suggested as intermediate vectors that might have carried SARS-CoV-2, or coronavirus precursors of it, to Wuhan; but neither a theory, nor a proximal spillover virus, nor a plausible intermediate host has gained significant support in the scientific community. The excellent reason is that data supporting them are largely lacking despite the apparently very intensive searching (Sallard et al., 2020).
          The most concrete of these zoonotic theories, and by far the most widely known, is the pangolin (Manis javanica) theory (Anderson et al., 2020; Lam et al., 2020; Xiao et al., 2020). It is proposed that pangolins smuggled from countries to the south of China harboured precursor coronaviruses picked up from bats, thereby bringing them to Wuhan.
          However, newly available evidence has made this scenario improbable. First, pangolins do not seem, after all, to naturally carry coronaviruses (Lee et al., 2020). Second, the pangolin theory rests largely on virus sequences obtained from pangolins confiscated in Guangdong province in early 2019. Attempted independent verification of these virus sequences has uncovered that, although four publications (now highly cited) discuss or report pangolin coronavirus sequences and therefore appear to support the widespread presence of coronaviruses in pangolins, only one virus genome was ever sequenced (Chan and Zhan, 2020). The papers by Xiao et al. (2020) and Liu et al. (2020) merely renamed and reconfigured sequence information generated by Liu et al. 2019. This is the same pangolin coronavirus data set discussed by Lam et al., 2020. Current thinking, in light of this new evidence, is that the smuggled pangolins were an ?incidental host? of the coronavirus. That is, the pangolins likely caught the virus while being smuggled (Chan and Zhan, 2020; Lee et al, 2020).
          In stark contrast, there are four distinct lab origin theories and these, unsurprisingly, are getting increasing attention. Two are published in the scientific literature (Sirotkin and Sirotkin, 2020; Segreto and Deigin, 2020). A third proposes that SARS-CoV-2 was a failed attempt to develop a vaccine. This theory was developed by an independent group of online researchers called DRASTIC. The fourth is our own Mojiang Miners Passage theory.
          This latter theory starts from the fact that viruses in the same mine where RaTG13 (the closest related viral sequence to SARS-CoV-2) was sampled appear to have given rise to a disease outbreak in 2012. In that outbreak, six miners were hospitalized with COVID-19-like symptoms and three died (Rahalkar and Bahulikar, 2020). All had been shovelling bat guano and were diagnosed at the time as likely suffering from an unknown coronavirus. Samples from four of the hospitalized miners were sent to the WIV for testing. To-date, there are conflicting claims about the results of those tests and nothing has been formally published (Zhou et al. 2020 addendum). The Mojiang Miners Passage theory proposes, however, that, by the time they arrived at the WIV, these patient-derived samples contained a highly adapted human virus, which subsequently escaped.
          For the present moment, notwithstanding the claim of the WHO investigation and the censorship of Facebook, all of these accidental lab origin theories appear plausible to us, but all remain uninvestigated. Our prediction, however, simply based on assessing the probabilities, is that no convincing natural zoonotic origin for the pandemic will ever be found by China or the WHO or anyone else??for the simple reason that one does not exist.
          References
          Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C., & Garry, R. F. (2020). The proximal origin of SARS-CoV-2. Nature medicine, 26(4), 450-452.
          Chan, Y. A., & Zhan, S. H. (2020). Single source of pangolin CoVs with a near identical Spike RBD to SARS-CoV-2. BioRxiv.
          S. G. of the International Committee on Taxonomy of Viruses (2020). The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nature microbiology, 5(4), 536.
          Graham, R. L., Donaldson, E. F., & Baric, R. S. (2013). A decade after SARS: strategies for controlling emerging coronaviruses. Nature Reviews Microbiology, 11(12), 836-848.
          Jiang, S., & Shi, Z. L. (2020). The first disease X is caused by a highly transmissible acute respiratory syndrome coronavirus. Virologica Sinica, 35(3), 263-265.
          Lam, T. T. Y., Jia, N., Zhang, Y. W., Shum, M. H. H., Jiang, J. F., Zhu, H. C., ? & Cao, W. C. (2020). Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature, 583(7815), 282-285.
          Lee, J., Hughes, T., Lee, M. H., Field, H., Rovie-Ryan, J. J., Sitam, F. T., ? & Daszak, P. (2020). No evidence of coronaviruses or other potentially zoonotic viruses in Sunda pangolins (Manis javanica) entering the wildlife trade via Malaysia. Ecohealth, 17(3), 406-418.
          Leitner, T., & Kumar, S. (2020). Where did SARS-CoV-2 come from?. Molecular biology and evolution, 37(9), 2463-2464.
          Li, H., Mendelsohn, E., Zong, C., Zhang, W., Hagan, E., Wang, N., ? & Daszak, P. (2019). Human-animal interactions and bat coronavirus spillover potential among rural residents in Southern China. Biosafety and Health, 1(2), 84-90.
          Li, B., Si, H. R., Zhu, Y., Yang, X. L., Anderson, D. E., Shi, Z. L., ? & Zhou, P. (2020). Discovery of bat coronaviruses through surveillance and probe capture-based next-generation sequencing. Msphere, 5(1).
          Liu, P., Chen, W., & Chen, J. P. (2019). Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). Viruses, 11(11), 979.
          Liu, P., Jiang, J. Z., Wan, X. F., Hua, Y., Li, L., Zhou, J., ? & Chen, J. (2020). Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)?. PLoS Pathogens, 16(5), e1008421.
          Rahalkar, M. C., & Bahulikar, R. A. (2020). Lethal pneumonia cases in Mojiang miners (2012) and the mineshaft could provide important clues to the origin of SARS-CoV-2. Frontiers in public health, 8, 638.
          Sallard, E., Halloy, J., Casane, D., Decroly, E., & van Helden, J. (2021). Tracing the origins of SARS-COV-2 in coronavirus phylogenies: a review. Environmental Chemistry Letters, 1-17.
          Seyran, M., Pizzol, D., Adadi, P., El?Aziz, T. M. A., Hassan, S. S., Soares, A., ? & Brufsky, A. M. (2020). Questions concerning the proximal origin of SARS?CoV?2. Journal of Medical Virology.
          Segreto, R., & Deigin, Y. (2020). The genetic structure of SARS?CoV?2 does not rule out a laboratory origin: SARS?COV?2 chimeric structure and furin cleavage site might be the result of genetic manipulation. BioEssays, 2000240.
          Sirotkin, K., & Sirotkin, D. (2020). Might SARS?CoV?2 have arisen via serial passage through an animal host or cell culture? A potential explanation for much of the novel coronavirus? distinctive genome. BioEssays, 42(10), 2000091.
          Wang, M., Yan, M., Xu, H., Liang, W., Kan, B., Zheng, B., ? & Xu, J. (2005). SARS-CoV infection in a restaurant from palm civet. Emerging infectious diseases, 11(12), 1860.
          Wang, N., Li, S. Y., Yang, X. L., Huang, H. M., Zhang, Y. J., Guo, H., ? & Shi, Z. L. (2018). Serological evidence of bat SARS-related coronavirus infection in humans, China. Virologica Sinica, 33(1), 104-107.
          Xiao, K., Zhai, J., Feng, Y., Zhou, N., Zhang, X., Zou, J. J., ? & Shen, Y. (2020). Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature, 583(7815), 286-289.
          Yu, P., Hu, B., Shi, Z. L., & Cui, J. (2019). Geographical structure of bat SARS-related coronaviruses. Infection, Genetics and Evolution, 69, 224-229.
          Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., ? & Shi, Z. L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. nature, 579(7798), 270-273.
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          Ask Congress to Investigate COVID Origins and Government Response to Pandemic.

          i love myself. the quietest. simplest. most powerful. revolution ever. ---- nayyirah waheed

          "...there’s an obvious contest that’s happening between different sectors of the colonial ruling class in this country. And they would, if they could, lump us into their beef, their struggle." ---- Omali Yeshitela, African People’s Socialist Party

          (My posts are not intended as advice or professional assessments of any kind.)
          Never forget Excalibur.

          Comment


          • Emily, this is not science, but ideology.
            How probabilities were there that the H1N1 pandemic emerged from a pig in Mexico? Pandemics are unpredictable and they come from where you least expect it

            Comment


            • Emily
              Emily commented
              Editing a comment
              I agree pandemics are unpredictable, yet the US, a country where little girls have to sell lemonade to finance their own brain surgeries, is spending hundreds of millions of dollars creating a fantasy that pandemics are predictable.

            • sharon sanders
              sharon sanders commented
              Editing a comment
              The authors seems to have an advocacy group: https://bioscienceresource.org/about...y-and-mission/ One is a virologist and one has a doctorate in molecular biology and genetics. Many scientists do not agree with each other and, in fact, there is quite a bit of professional arguing on many topics among them. This is why we have advised for years for people to use at least two sources for their information. I also agree that pandemics are unpredictable. And I am still waiting for an intermediary animal to be identified for SARS-CoV-2.

          • But what has not been foregrounded is that, even within the coronaviruses, Zheng-li Shi?s laboratory had, of the 28 relevant coronavirus species, singled out just one of them as their special focus. And it is a member of this species (called the ?SARS-related coronaviruses?) that broke out in Wuhan in 2019.
            What gets researched is what you can get funding for.
            China, and the world, had a major scare with the emergence of SARS-1 after which there was a considerable investment in trying to find its origins, vaccines, therapeutics and detection systems. Many new researches entered the Corona virus field but once it was eradicated most of the money disappeared and they had to stop and find a new areas to work in where they could get funding. All vaccines and therapeutics stopped, at what ever point they had reached, and the CoV basic research returned to a slightly higher level than it had been before the outbreak. The same happened after the investments in pandemic planning and PPE stock piles generated after the 2005 H5N1 scare. That the WIV was working on sarbecovs is no coincidence as the last spike in interest was due to an epidemic from this group and the host reservoir was from a bat species found within its boarders. Alpha CoVs are thought to be an equally likely source for the next CoV epidemic as they also have a genomic constellation with sequences close to the bat/human zoonotic interface and will probably be easier to get funding to work on as SADS (alphaCoV) jumped to pigs in 2016 and is causing major economic losses (which is what counts). The good news is that the funding post SARS1, while it lasted, is why we already had a head start in vaccine and basic science research, without which we would not have vaccines so quickly, it also funded the national 'pneumonia of unknown cause' reporting mechanism which allowed for the early identification of a small spike in cases in Wuhan against the normal background.

            Comment



            • Scientists Chasing Origins of COVID-19 Add Southeast Asia to Search

              March 22, 2021 07:33 AM
              By Zsombor Peter

              KUALA LUMPUR - Scientists hunting the origins of the virus behind COVID-19 and clues for how to prevent the next pandemic say a growing body of evidence argues for expanding the search beyond China into Southeast Asia.

              Since the first confirmed outbreak of COVID-19 put the eastern Chinese city of Wuhan on the world map in December 2019, researchers looking for the source of the virus that causes the disease, SARS-CoV-2, have been training their gaze on China itself.

              The pathogen?s closest known relative, sharing some 96% of its genome, is another coronavirus found early last year in the southern province of Yunnan

              But a spate of recent studies has found more viruses nearly as similar to SARS-CoV-2 as the one in Yunnan further afield, in Thailand and Cambodia.

              ... The strains found in Thailand and Cambodia, ?could be the ancestor or something close to the ancestor of SARS-COVID-2,? he told VOA.

              ?That?s why now maybe more work has to be carried out on this region to see whether we can identify any intermediate hosts that carry [a virus with] 99.9% genome similarity to the SARS-COVID-2.?

              Close relatives of the virus causing the pandemic have cropped up in Thailand and Cambodia, raising the odds of an origin outside of China

              Comment


              • PHAC president given until Friday to explain why two scientists were let go

                Joan Bryden
                Published Monday,March 22, 2021 9:08PM EDT

                OTTAWA -- The president of the Public Health Agency of Canada has been given until the end of the week to explain why two Canadian government scientists were let go 18 months after being escorted from Canada's only Level 4 laboratory.

                Iain Stewart came under fire Monday from opposition MPs after he repeatedly refused to explain why PHAC terminated the employment of Dr. Xiangguo Qiu and her husband, Keding Cheng, in January.

                Stewart told the special committee on Canada-China relations that he could not provide details due to privacy issues and "security with respect to the investigation" still being conducted by the RCMP....

                ....The pair were escorted out of the National Microbiology Laboratory in July 2019 over what was described as a possible policy breach and administrative matter.

                The Winnipeg lab is Canada's highest-security laboratory, designed to deal safely with deadly contagious germs such as Ebola....

                ..PHAC has said their escorted exit had nothing to do with the fact that four months earlier, Qiu had been responsible for a shipment of Ebola and Henipah viruses to China's Wuhan Institute of Virology....https://www.ctvnews.ca/politics/phac...t-go-1.5358099
                CSI:WORLD http://swineflumagazine.blogspot.com/

                treyfish2004@yahoo.com

                Comment


                • bump this

                  Comment


                  • I posted the first study (e-print) in April 2020. It was later revised in November 2020. The second study is from March 2021.

                    e-print
                    [Submitted on 13 May 2020 (v1), last revised 21 Nov 2020 (this version, v2)]

                    In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities
                    across species and implications for viral origin


                    Sakshi Piplani1,2, Puneet Kumar Singh2
                    , David A. Winkler3-6
                    *, Nikolai Petrovsky1,2*
                    1 College of Medicine and Public Health, Flinders University, Bedford Park 5046, Australia
                    2 Vaxine Pty Ltd, 11 Walkley Avenue, Warradale 5046, Australia
                    3 La Trobe University, Kingsbury Drive, Bundoora 3086, Australia
                    4 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia
                    5 School of Pharmacy, University of Nottingham, Nottingham NG7 2RD. UK
                    6 CSIRO Data61, Pullenvale 4069, Australia
                    *Joint senior authors
                    Corresponding authors: ?
                    Prof. Nikolai Petrovsky: nikolai.petrovsky@flinders.edu.au
                    Prof. Dave Winkler: d.winkler@latrobe.edu.au
                    ...

                    Our data indicates that the earliest isolates of SARS-CoV-2 were
                    surprisingly well adapted to human ACE2, potentially explaining its rapid transmission.

                    ...
                    Our structure-based approach revealed some surprisingly results, contrasting with to those from
                    sequence based analyses. Conspicuously, the predicted binding between SARS-CoV-2 S protein
                    11 and ACE2 was strongest overall for humans than for any species studied.
                    The predicted strength of
                    SARS-CoV-2 S protein binding to ACE2 being human > pangolin > dog > monkey > hamster >
                    ferret > cat> tiger > bat > civet > horse > cow > snake > mouse ACE2.

                    Spike protein mutations are rare, especially in the receptor binding domain (RBD) that interacts
                    with ACE2. For the SARS-Cov-2 S protein, only three mutational sites, V367F, G476S, and
                    V483A, have been identified within the RBD domain. Of these, only G476S occurs directly at the
                    binding interface of RBD and the peptidase domain of ACE2 and its incidence and geographic
                    spread is very small.40 This minimal mutation in the spike RBD during the history of the pandemic
                    suggests that the spike RBD was already optimally adapted to bind human ACE2. This finding is
                    surprising as, typically, a virus exhibits the highest affinity for receptors in its original host species,
                    presumed by most to be bat, with a lower initial affinity for the receptor of any new host species
                    such as humans. Then as the virus mutates and adapts to its new host species, the binding affinity
                    might be expected to increase over time. Since our calculations are based on SARS-Cov-2 S
                    sequences samples isolated in December and hence from very early in the outbreak, the finding that
                    the affinity of SARS-CoV-2 S protein is higher for human ACE2 than for any other putative host
                    species was unexpected.


                    This very high affinity for human ACE2 was confirmed very recently (July 10) in a preprint by
                    Alexander et al.41 who also studied the RBD of spike-ACE2 for several species and reported that
                    the SARS-CoV-2 RBD sequence is optimal for binding to human ACE2 compared to other species.

                    They also described this as a remarkable finding that underlies the high transmissibility of the SARCov-2
                    virus amongst humans. These results are also consistent with a recent report comparing
                    SARS-CoV and SARS-CoV-2 that found a number of differences in the SARS-CoV-2 RBD that
                    made it a much more potent binder to human ACE2 through the introduction of numerous hydrogen
                    bonding and hydrophobic networks35 helping explain the efficient and rapid transmission SARSCoV-2
                    through the human population, once a presumed cross-over event occurred in or around
                    November 2019.
                    ...
                    Implications for the intermediate animal vector for SARS-Cov-2

                    Bats have been suggested as the original host species of SARS-Cov-2 infections in humans,
                    with pangolins acting as an intermediate animal vector. Bat CoV RaTG13 has the highest sequence
                    similarity to SARS-CoV-2, with 96% whole-genome identity (50)
                    ., but does not possess neither the furin cleavage site or the pangolin RBD seen in SARS-CoV-2. Could SARS-CoV-2 be an as-yet
                    unidentified bat virus? Although bats carry many coronaviruses, no evidence of a direct relative of
                    SARS-CoV-2 in bat populations has so far been found. As highlighted by our data, the binding
                    affinity of SARS-CoV-2 for bat ACE2 is considerably lower than for human ACE2 and human
                    ACE2 has been shown to not to bind the RaTG13 spike 53. This suggests that even if SARS-CoV-2
                    did originally arise from a bat precursor, it must have spent considerable time in another host
                    wherein it adapted its S protein to bind better to the host ACE2. This also resulted in acquiring
                    higher affinity for human ACE2 while lowering its affinity to the original bat ACE2. There are
                    currently no known explanations for how or where this transition to generate the ultimate SARSCoV-2 spike
                    protein could have occurred. Evidence of direct human infection by bat coronaviruses
                    or other viruses is rare, with transmission typically involving an intermediate host.
                    For example,
                    SARS-CoV was shown to be transmitted from bats to civet cats and then to humans. The S protein
                    must acquire new mutations to enable this transition to occur, first to increase its affinity for civet
                    ACE2 and then to increase its affinity for human ACE2. To date, a virus directly related to SARSCoV-2
                    has not been identified in bats or any other non-human species, making its origins unclear.
                    ...
                    This study concluded, based on available genome sequence data, that the
                    current epidemic has been driven entirely by human to human transmission
                    at least since December.
                    As the SARS-CoV-2 structure that we employed was obtained from viruses collected early in the
                    outbreak, it is not clear how these early strains of SARS-CoV-2 developed such a high affinity for
                    human ACE2. This suggests that SARS-CoV-2 spike RBD previously evolved by selection on a
                    human-like ACE2.
                    Notably, pangolin ACE2 bears major differences in its RBD to human ACE2.
                    Therefore its is surprising that pangolin-CoV has a similar RBD to SARS-CoV-2 that forms the
                    basis for implicating pangolins directly or indirectly in the origins of SARS-CoV-2. The fact that
                    pangolin CoVs can use human ACE2 for cell entry suggests that pangolin CoVs could represent a
                    source of future human coronavirus pandemics if they were to gain the SARS-CoV-2 furin
                    cleavage site.

                    Given the seriousness of the ongoing SARS-CoV-2 pandemic, it is imperative that all efforts be
                    made to identify the original source of the virus. One question to be addressed is whether the virus
                    is completely natural and was transmitted to humans by an intermediate animal vector, or whether it
                    came from a recombination event that occurred inadvertently or intentionally in a laboratory
                    handling coronaviruses, with the new virus being inadvertently released into the local human
                    population.
                    .

                    ...

                    The devastating impact of the COVID-19 pandemic caused by SARS coronavirus 2 (SARS CoV 2) has raised important questions about viral origin, mechanisms of zoonotic transfer to humans, whether companion or commercial animals can act as reservoirs for infection, and why there are large variations in SARS-CoV-2 susceptibilities across animal species. Powerful in silico modelling methods can rapidly generate information on newly emerged pathogens to aid countermeasure development and predict future behaviours. Here we report an in silico structural homology modelling, protein-protein docking, and molecular dynamics simulation study of the key infection initiating interaction between the spike protein of SARS-Cov-2 and its target, angiotensin converting enzyme 2 (ACE2) from multiple species. Human ACE2 has the strongest binding interaction, significantly greater than for any species proposed as source of the virus. Binding to pangolin ACE2 was the second strongest, possibly due to the SARS-CoV-2 spike receptor binding domain (RBD) being identical to pangolin CoV spike RDB. Except for snake, pangolin and bat for which permissiveness has not been tested, all those species in the upper half of the affinity range (human, monkey, hamster, dog, ferret) have been shown to be at least moderately permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and permissiveness. Our data indicates that the earliest isolates of SARS-CoV-2 were surprisingly well adapted to human ACE2, potentially explaining its rapid transmission.

                    ------------------------------------------------------------------------------------------------


                    Hat tip Tetano

                    Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

                    Yinghui Liu, Gaowei Hu, Yuyan Wang, View ORCID ProfileWenlin Ren, Xiaomin Zhao, Fansen Ji, Yunkai Zhu, Fei Feng, Mingli Gong, View ORCID ProfileXiaohui Ju, Yuanfei Zhu, Xia Cai, Jun Lan, View ORCID ProfileJianying Guo, Min Xie, Lin Dong, Zihui Zhu, Jie Na, View ORCID ProfileJianping Wu, Xun Lan, Youhua Xie, Xinquan Wang, Zhenghong Yuan, Rong Zhang, and Qiang Ding
                    See all authors and affiliations

                    PNAS March 23, 2021 118 (12) e2025373118; https://doi.org/10.1073/pnas.2025373118
                    Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, New York, and approved February 5, 2021 (received for review December 10, 2020)

                    Article Figures & SI Info & Metrics PDF

                    Significance

                    COVID-19, caused by SARS-CoV-2, is a major global health threat. The host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. We found that SARS-CoV-2 has the potential to infect a broad range of mammalian hosts, including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria. Those species may be at risk for human-to-animal or animal-to-animal transmissions of SARS-CoV-2. Our study highlights the importance of banning illegal wildlife trade and consumption, and enforcing the importance of surveilling animals in close contact with humans as potential zoonotic reservoirs to prevent outbreaks in the future.

                    Abstract

                    The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs?including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria?could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.
                    ...

                    ...


                    Proc Natl Acad Sci U S A . 2021 Mar 23;118(12):e2025373118. doi: 10.1073/pnas.2025373118. Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2 Yinghui Liu (https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Liu+Y&cauthor_id=33658332) 1 (https://pubmed.ncbi.
                    "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
                    -Nelson Mandela

                    Comment


                    • JJackson
                      JJackson commented
                      Editing a comment
                      Beta CoVs have been regularly infecting humans but apart from SARS-1 & 2 have not been able to sustain H2H and have died out. It is not know what cell receptor these viruses use in their bat hosts but it is probably not ACE2 which has allowed a great deal of variation in the spike as it is not of great significance in its natural host. The wide divergence found in RaTG13, from most sarbetacovs, is likely to not have been a particular problem for it as it is unlikely to have much of an impact in bats. Similarly what ever mutation the progenitor of the SARS-2 had would not effect its replication in bats to a great extent but would have made it the one human, or other animal, infection able to sustain some level of host-to-host transmission until it hit on the form that allowed it to start the pandemic, likewise for the earlier jump into pangolins. None of this is likely to have happened in Wuhan as its geology does not support the caves used by the bats. The massive sandstone formations in Yunnan are where the caves, and bats, are located and the high seroprevalence in humans is found but this is about 1000km from Wuhan. The other human beta coronaviruses use various receptors MERS (CD26), OC43 & HKU1 (9-O-acetylated sialic acid) and SARS (ACE2)

                  • Pathfinder.. that story was made up a can?t be true!
                    CSI:WORLD http://swineflumagazine.blogspot.com/

                    treyfish2004@yahoo.com

                    Comment


                    • Animal Origins of the Severe Acute Respiratory Syndrome Coronavirus: Insight from ACE2-S-Protein Interactions



                      CONCLUSIONS

                      The intense scientific effort expended in describing SARS and SARS-CoV has provided a unique case study in viral evolution and zoonotic transmission. The SARS-CoV example underscores the need in some instances for a bridge species that is in direct contact with humans and that may guide virus evolution so as to permit emergence of a variant that can transmit efficiently among humans.

                      It highlights viral strategies that permit rapid adaptation to new species and shows that mildly pathogenic viruses may not remain so with changes in human and animal populations which increase viral diversity or the frequency of cross-species contacts. Experience with SARS-CoV has demonstrated the importance of field work that identifies and characterizes viruses and host factors in wild and domesticated animals. Further work in these directions may help anticipate and avoid the next SARS.

                      Important questions remain. What receptor does bat SARS-CoV utilize? If bats are indeed a reservoir of SARS-CoV-like viruses, when and in which species did these viruses acquire an S protein capable of using palm civet and human ACE2? Did SARS-CoV gain the use of ACE2 through recombination, and if so, with what virus? Are changes in the S protein that enhanced human-to-human transmission a probable consequence of incubation in palm civets and other animals or a unique event unlikely to recur? What changes in other viral proteins were necessary for SARS-CoV to transmit efficiently among humans?

                      Study of SARS-CoV suggests we should direct our attention to adaptation strategies themselves, such as reassortment (for influenza viruses) and recombination (for coronaviruses), rather than to the end products of these adaptations. It also suggests that further attention should be given to the possible emergence of dangerous variants of common pathogens, such as HCoV-NL63 and its animal equivalents. In short, there are more lessons to learn from SARS.
                      • Copyright ? 2006 American Society for Microbiology
                      ?Addressing chronic disease is an issue of human rights ? that must be our call to arms"
                      Richard Horton, Editor-in-Chief The Lancet

                      ~~~~ Twitter:@GertvanderHoek ~~~ GertvanderHoek@gmail.com ~~~

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