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Genetic samples from the market were recently uploaded to an international database and then removed after scientists asked China about them. An international team of virus experts said on Thursday that they had found genetic data from a market in Wuhan, China, linking the coronavirus with raccoon dogs for sale there, adding evidence to the case that the worst pandemic in a century could have been ignited by an infected animal that was being dealt through the illegal wildlife trade. The genetic data was drawn from swabs taken from in and around the Huanan Seafood Wholesale Market starting in January 2020, shortly after the Chinese authorities had shut down the market because of suspicions that it was linked to the outbreak of a new virus. By then, the animals had been cleared out, but researchers swabbed walls, floors, metal cages and carts often used for transporting animal cages. In samples that came back positive for the coronavirus, the international research team found genetic material belonging to animals, including large amounts that were a match for the raccoon dog, three scientists involved in the analysis said. The jumbling together of genetic material from the virus and the animal does not prove that a raccoon dog itself was infected. And even if a raccoon dog had been infected, it would not be clear that the animal had spread the virus to people. Another animal could have passed the virus to people, or someone infected with the virus could have spread the virus to a raccoon dog. But the analysis did establish that raccoon dogs — fluffy animals that are related to foxes and are known to be able to transmit the coronavirus — deposited genetic signatures in the same place where genetic material from the virus was left, the three scientists said. That evidence, they said, was consistent with a scenario in which the virus had spilled into humans from a wild animal. A report with the full details of the international research team’s findings has not yet been published. Their analysis was first reported by The Atlantic. The new evidence is sure to provide a jolt to the debate over the pandemic’s origins, even if it does not resolve the question of how it began. In recent weeks, the so-called lab leak theory, which posits that the coronavirus emerged from a research lab in Wuhan, has gained traction thanks to a new intelligence assessment from the U.S. Department of Energy and hearings led by the new Republican House leadership. But the genetic data from the market offers some of the most tangible evidence yet of how the virus could have spilled into people from wild animals outside a lab. It also suggests that Chinese scientists have given an incomplete account of evidence that could fill in details about how the virus was spreading at the Huanan market. Jeremy Kamil, a virologist at Louisiana State University Health Sciences Center Shreveport who was not involved in the study, said the findings showed that “the samples from the market that had early Covid lineages in them were contaminated with DNA reads of wild animals.” Dr. Kamil said that fell short of conclusive evidence that an infected animal had set off the pandemic. But, he said, “it really puts the spotlight on the illegal animal trade in an intimate way.” Chinese scientists had released a study looking at the same market samples in February 2022. That study had reported that samples were positive for the coronavirus but suggested that the virus had come from infected people who were shopping or working in the market, rather than from animals being sold there. At some point, those same researchers, including some affiliated with the Chinese Center for Disease Control and Prevention, posted the raw data from swabs around the market to GISAID, an international repository of genetic sequences of viruses. (Attempts to reach the Chinese scientists by phone on Thursday were not successful.) On March 4, Florence Débarre, an evolutionary biologist at the French National Center for Scientific Research, happened to be searching that database for information related to the Huanan market when, she said in an interview, she noticed more sequences than usual popping up. Confused at first about whether they contained new data, Dr. Débarre put them aside, only to log in again last week and discover that they held a trove of raw data. Virus experts had been awaiting that raw sequence data from the market since they learned of its existence in the Chinese report from February 2022. Dr. Débarre said she had alerted other scientists, including the leaders of a team that had published a set of studies last year pointing to the market as the origin.An international team — which included Michael Worobey, an evolutionary biologist at the University of Arizona; Kristian Andersen, a virologist at the Scripps Research Institute in California; and Edward Holmes, a biologist at the University of Sydney — started mining the new genetic data last week. One sample in particular caught their attention. It had been taken from a cart linked to a specific stall at the Huanan market that Dr. Holmes had visited in 2014, scientists involved in the analysis said. That stall, Dr. Holmes found, contained caged raccoon dogs on top of a separate cage holding birds, exactly the sort of environment conducive to the transmission of new viruses. The swab taken from a cart there in early 2020, the research team found, contained genetic material from the virus and a raccoon dog. “We were able to figure out relatively quickly that at least in one of these samples, there was a lot of raccoon dog nucleic acid, along with virus nucleic acid,” said Stephen Goldstein, a virologist at the University of Utah who worked on the new analysis. (Nucleic acids are the chemical building blocks that carry genetic information.) After the international team stumbled upon the new data, they reached out to the Chinese researchers who had uploaded the files with an offer to collaborate, hewing to rules of the online repository, scientists involved with the new analysis said. After that, the sequences disappeared from GISAID. It is not clear who removed them or why they were taken down. Dr. Débarre said the research team was seeking more data, including some from market samples that were never made public. “What’s important is there’s still more data,” she said. Scientists involved with the analysis said that some of the samples had also contained genetic material from other animals and from humans. Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan in Canada, who worked on the analysis, said that the human genetic material was to be expected given that people were shopping and working there and that human Covid cases had been linked to the market. Dr. Goldstein, too, cautioned that “we don’t have an infected animal, and we can’t prove definitively there was an infected animal at that stall.” Genetic material from the virus is stable enough, he said, that it is not clear when exactly it was deposited at the market. He said that the team was still analyzing the data and that it had not intended for its analysis to become public before it had released a report. “But,” he said, “given that the animals that were present in the market were not sampled at the time, this is as good as we can hope to get.”
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The conclusion, which was made with “low confidence,” came as America’s intelligence agencies remained divided over the origins of the coronavirus. WASHINGTON — New intelligence has prompted the Energy Department to conclude that an accidental laboratory leak in China most likely caused the coronavirus pandemic, though U.S. spy agencies remain divided over the origins of the virus, American officials said on Sunday. The conclusion was a change from the department’s earlier position that it was undecided on how the virus emerged. Some officials briefed on the intelligence said that it was relatively weak and that the Energy Department’s conclusion was made with “low confidence,” suggesting its level of certainty was not high. While the department shared the information with other agencies, none of them changed their conclusions, officials said. Officials would not disclose what the intelligence was. But many of the Energy Department’s insights come from the network of national laboratories it oversees, rather than more traditional forms of intelligence like spy networks or communications intercepts. Intelligence officials believe the scrutiny of the pandemic’s beginnings could be important to improving global response to future health crises, though they caution that finding an answer about the source of the virus may be difficult or even impossible given Chinese opposition to further research. Scientists say there is a responsibility to explain how a pandemic that has killed almost seven million people started, and learning more about its origins could help researchers understand what poses the biggest threats of future outbreaks. The new intelligence and the shift in the department’s view was first reported by The Wall Street Journal on Sunday. Jake Sullivan, the national security adviser, declined to confirm the intelligence. But he said President Biden had ordered that the national labs be brought into the effort to determine the origins of the outbreak so that the government was using “every tool” it had. In addition to the Energy Department, the F.B.I. has also concluded, with moderate confidence, that the virus first emerged accidentally from the Wuhan Institute of Virology, a Chinese lab that worked on coronaviruses. Four other intelligence agencies and the National Intelligence Council have concluded, with low confidence, that the virus most likely emerged through natural transmission, the director of national intelligence’s office announced in October 2021. Mr. Sullivan said those divisions remain. “There is a variety of views in the intelligence community,” he said on CNN’s “State of the Union” on Sunday. “Some elements of the intelligence community have reached conclusions on one side, some on the other. A number of them have said they just don’t have enough information to be sure.” Mr. Sullivan said if more information was learned, the administration would report it to Congress and the public. “But right now, there is not a definitive answer that has emerged from the intelligence community on this question,” he said. Some scientists believe that the current evidence, including virus genes, points to a large food and live animal market in Wuhan as the most likely place the coronavirus emerged. Leaders of the intelligence community are set to brief Congress on March 8 and 9 as part of annual hearings on global threats. Avril D. Haines, the director of national intelligence, and other senior officials would most likely be asked about the continuing inquiry into the virus’s origins. How the pandemic began has become a divisive line of intelligence reporting, and recent congressional reports have not been bipartisan. Many Democrats have not been persuaded by the lab leak hypothesis, with some saying they believe the natural causes explanation and others saying they are not certain that enough intelligence will emerge to draw a conclusion. But many Republicans on Capitol Hill have said they believe the virus could have come from one of China’s research labs in Wuhan. A congressional subcommittee, created when Republicans took over the House in January, has made examining the lab leak theory a central focus of its work. It is expected to convene the first of a series of hearings in March “Evidence has been piling up for over a year in favor of the lab leak hypothesis,” said Representative Mike Gallagher, a Wisconsin Republican who sits on the House Intelligence Committee and leads a new House committee on China. “I am glad some of our agencies are starting to listen to common sense and change their assessment.” On Tuesday, Mr. Gallagher will hold the new committee’s first hearing, looking at the threat the Chinese Communist Party poses to the United States. Future hearings, Mr. Gallagher said, will look at biosecurity and China’s efforts to influence international organizations like the World Health Organization. “Where our committee can have a role is teasing out what this communicates about the DNA of the Chinese Communist Party, an organization that was willing to cover up the origins of the pandemic and thereby cost us critical days, months and weeks and millions of lives in the process,” Mr. Gallagher said in an interview on Sunday. Chinese officials have repeatedly called the lab leak hypothesis a lie that has no basis in science and is politically motivated. Early in the Biden administration, the president ordered the intelligence agencies to investigate the pandemic’s origins, after criticism of a W.H.O. report on the matter. While there was material that had not been thoroughly examined by intelligence officials, the review ultimately did not yield any new consensus inside the agencies. The March 2021 report by the W.H.O. said it was “extremely unlikely” that the virus emerged accidentally from a lab. But China appointed half the scientists who wrote the report and exerted major control over it. American officials have been largely dismissive of that work. The intelligence agencies have said they do not believe there is any evidence that the coronavirus that causes Covid-19 was created deliberately as a biological weapon. But they have said that whether it emerged naturally, perhaps from a market in Wuhan, or escaped accidentally from a lab is the subject of legitimate debate. Anthony Ruggiero, a scholar at the Foundation for Defense of Democracies and a former National Security Council staff member focusing on biodefense issues during the Trump administration, said he believed China is still “hiding crucial information” about how the virus emerged. He said the lab leak theory should not be dismissed. “The lab leak origin for the Covid-19 pandemic is not, and was not, a conspiracy theory,” he said. Benjamin Mueller and Sheryl Gay Stolberg contributed reporting.
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Significance Tracking the animal reservoir of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants is important for understanding the current COVID-19 pandemic and preventing future pandemics. Speculations about the source of the omicron variant are abundant, yet experimental evidence has been scarce. Here, we provide the structural information on how omicron recognizes its mouse receptor. Our study demonstrates that the omicron mutations in the receptor-binding region are structurally adapted to mouse angiotensin-converting enzyme 2 (ACE2), informing an understanding of the origin of the omicron variant and the evolution of SARS-CoV-2. It may facilitate epidemiological surveillance of SARS-CoV-2 in animals to prevent future coronavirus pandemics. Abstract The sudden emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant has raised questions about its animal reservoir. Here, we investigated receptor recognition of the omicron’s receptor-binding domain (RBD), focusing on four of its mutations (Q493R, Q498R, N501Y, and Y505H) surrounding two mutational hotspots. These mutations have variable effects on the RBD’s affinity for human angiotensin-converting enzyme 2 (ACE2), but they all enhance the RBD’s affinity for mouse ACE2. We further determined the crystal structure of omicron RBD complexed with mouse ACE2. The structure showed that all four mutations are viral adaptations to mouse ACE2: three of them (Q493R, Q498R, and Y505H) are uniquely adapted to mouse ACE2, whereas the other one (N501Y) is adapted to both human ACE2 and mouse ACE2. These data reveal that the omicron RBD was well adapted to mouse ACE2 before omicron started to infect humans, providing insight into the potential evolutionary origin of the omicron variant. Published in PNAS (Oct.18, 2022):
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Two new studies say the virus was present in animals at the Huanan seafood market in 2019. Scientists released a pair of extensive studies on Saturday that point to a market in Wuhan, China, as the origin of the coronavirus pandemic. Analyzing data from a variety of sources, they concluded that the coronavirus was very likely present in live mammals sold in the Huanan Seafood Wholesale Market in late 2019 and suggested that the virus twice spilled over into people working or shopping there. They said they found no support for an alternate theory that the coronavirus escaped from a laboratory in Wuhan. “When you look at all of the evidence together, it’s an extraordinarily clear picture that the pandemic started at the Huanan market,” said Michael Worobey, an evolutionary biologist at the University of Arizona and a co-author of both studies. The two reports have not yet been published in a scientific journal that would require undergoing peer review. Together, they represent a significant salvo in the debate over the beginnings of a pandemic that has killed nearly 6 million people globally and sickened more than 400 million. The question of whether the coronavirus outbreak began with a spillover from wildlife sold at the market, a leak from a Wuhan virology lab or some other way has given rise to pitched geopolitical battles and debates over how best to stop the next pandemic. But some outside scientists who have been hesitant to endorse the market origin hypothesis said they remained unconvinced. Jesse Bloom, a virologist at the Fred Hutchinson Cancer Research Center, said in an interview that there remained a glaring absence of direct evidence that animals at the market had themselves been infected with the coronavirus. “I think what they’re arguing could be true,” Dr. Bloom said of the new studies. “But I don’t think the quality of the data is sufficient to say that any of these scenarios are true with confidence.” In their new study, Dr. Worobey and his colleagues present evidence that wild mammals that might have harbored the coronavirus were being sold in December 2019. But no wildlife was left at the market by the time Chinese researchers arrived in early 2020 to collect genetic samples... Preprints cited available at (Feb.25, 2022) https://zenodo.org/record/6299600#.YhsH6e7MKLH https://www.researchsquare.com/article/rs-1370392/v1
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A Chinese virologist and whistleblower on Monday (Sept. 14) followed through on her pledge to release a paper explaining how the genome of the Wuhan coronavirus (COVID-19) indicates that it was constructed in a Chinese lab rather than naturally occurring. For the past few months, Yan Li-Meng (閻麗夢), a virologist employed as a researcher at the University of Hong Kong's School of Public Health when the coronavirus pandemic began, has been alleging that the coronavirus came from a Chinese lab and that it is a chimera based on the "Zhoushan bat coronavirus." According to Yan, an examination of the genome sequences released by the Chinese government on Jan. 14 also shows that the Zhoushan ZC45 and ZXC21 strains are the closest to SARS-CoV-2 and that they are the "backbone" upon which COVID-19 was constructed. In August, Yan claimed that she and her team had produced a scientific report that shows the origin of COVID-19 is the "PLA-owned Zhoushan bat coronavirus." She stated that she planned to release the report in the near future, and accused the World Health Organization (WHO) of "covering up numerous lies for the CCP." On Monday, Yan released the report on the data platform Zenodo with the title "Unusual Features of the SARS-CoV-2 Genome Suggesting Sophisticated Laboratory Modification Rather Than Natural Evolution and Delineation of Its Probable Synthetic Route." Zenodo is a general open access repository developed under the European OpenAIRE project and operated by the European Organization for Nuclear Research (CERN), allowing researchers to store data, software, reports, and any research-related tools. In the abstract, Yan's team pointed out that despite the fact that COVID-19 (SARS-CoV-2) has claimed the lives of over 900,000 people and devastated the global economy, the origin of the virus remains a mystery and highly controversial. The theory that the virus originated in nature is widely accepted, despite the lack of solid evidence, while suggestions that the disease may have come from a laboratory have been strictly censored from scientific journals, according to the report. The paper pointed out that the biological characteristics of SARS-CoV-2 are not consistent with a naturally occurring zoonotic virus. The researchers assert that the genomic, structural, medical, and literaty evidence presented in the paper strongly contradicts the natural origin theory. As previously mentioned by Yan, the researchers claim that evidence provided in the report point to the ZC45 and ZXC21 bat coronaviruses as the model or base for the chimera that became SARS-CoV-2. Furthermore, the authors postulate that the steps needed to produce the virus synthetically in a laboratory can be achieved in "approximately six months." The scientists then call for an independent investigation into China's virology laboratories, particularly gain-of-function research carried out at the Wuhan Institue of Virology (WIV). In Part 1 of the paper, the scientists provide evidence that the SARS-CoV-2 was subjected to in vitro manipulation. First, it states that the genomic sequence of the virus is strikingly similar to that of a bat coronavirus found by People's Liberation Army (PLA) labs in the Third Military Medical University in Chongqing, China, and the Research Institute for Medicine of Nanjing Command in Nanjing, China. Second, it shows that the receptor-binding motif (RBM) found in the virus's notorious spike protein is "suspiciously" similar to SARS-CoV from the 2003 SARS outbreak, indicating it was genetically modified. Third, the spike protein of the virus contains a unique furin cleavage site that is "completely absent in this particular class of coronaviruses found in nature," while the rare codons seen in this sequence suggest that it could have been inserted into the genome artificially. Regarding the "Zhoushan bat virus," the team wrote that ZC45 and ZXC2 have the highest sequence identity with SARS-CoV-2. In terms of similarity between ZC45/ZXC2 and SARS-CoV-2, the genome is 97 percent identical, the nucleocapsid protein is 94 percent identical, the membrane protein is 98.6 percent identical, and the S2 portion (2nd half) of the spike protein is 95 percent identical. The paper emphasized that the Orf8 protein is 94.2 percent identical, while the E protein is 100 percent identical. The Orf8 is highly unusual in coronaviruses, while no other known coronaviruses share 100 percent of the E protein with SARS-CoV-2 besides ZC45/ZXC2. The study excludes the RaTG13 virus submitted by WIV scientist Shi Zhengli, also known as "Bat Woman," because recent research has shown that its spike protein cannot bind to the angiotensin-converting enzyme 2 (ACE2) of two types of horseshoe bats, the alleged natural host, indicating that it may be "fabricated to shift the attention away from m ZC45/ZXC2. In Part 2 of the paper, the researches describe how SARS-CoV-2 could be designed and "created conveniently" in laboratories using the ZC45/ZXC2 viruses as the backbone. The scientists postulate that Step 1 consisted of replacing the RBM with a "designed and possibly optimized RBM" using that of SARS-CoV as a guide to enable it to bind with the human angiotensin-converting enzyme 2 (hACE2). The authors pointed out that Shi, along with long-term partner and structural biology specialist Fang Li, had successfully modified the RBM in this way. The report estimates that this first phase would take about one and a half months. Step 2 would consist of engineering a furin cleavage site at the S1/S2 junction of the spike protein. According to the researchers, this short stretch of gene sequence can be "conveniently inserted" using a number of standard cloning techniques, such as "QuikChange Site-Directed PCR60, overlap PCR followed by restriction enzyme digestion and ligation91, or Gibson assembly." The authors stated that none of these methods would leave any trace in the sequence. This further modification of the spike, including the furin-cleavage site, could be completed in "no more than two weeks," according to the report. Step 3 could be carried out simultaneously with the previous steps and would consist of acquiring an ORF1b gene that holds the RdRpgene segment from RaBtCoV/4991, a bat coronavirus discovered in 2013. The authors believe that that the Chinese virologists wanted the RdRp protein either to ensure that the resulting chimera would be classified in different groups/sub-lineages than ZC45/ZXC2 in phylogenetic studies or to test antiviral drugs. Step 4 would involve using reverse genetics to produce the chimera and recover live viruses within the course of two weeks. The authors cited an example of how a Swiss team was able to reconstruct the entire SARS-CoV-2 genome using transformation-assisted recombination in yeast within a single week. Significantly, this method has been available since 2017 and "would not leave any trace of artificial manipulation in the created viral genome." The paper also mentioned that the WIV has used alternative methods of reverse genetics in the past. Step 5, and the final step in the process, is to optimize the virus for its hACE2 binding affinity (ability to infect humans) with experiments on live animals. This normally consists of infecting rodents, such as hACE2 transgenic mice (hACE2-mice), with the virus and extracting the highest viral load from 10 to 15 rounds of passage to obtain the strain with the optimal hACE2-binding affinity. However, the authors of this report postulate that the Chinese scientists failed to use a "proper animal model" when testing the transmissibility of the virus. If they had, the scientists say the highly contentious nature of SARS-CoV-2 would have been obvious and the early claims of "not causing human-to-human transmission" would have not been made at the start of the pandemic. The researchers suggest that "extensive laboratory-adaption" geared toward augmented transmissibility and lethality "may have driven the virus too far." The scientists believe that the virus might have lost the "capacity to [attenuate] both transmissibility and lethality during its current adaptation in the human population," as evidenced by the lack of attenuation by the virus despite its extensive spread globally and the emergence of a variant with "improved transmissibility." Manuscript uploaded to Zenodo (Sept. 14, 2020): https://zenodo.org/record/4028830#.X2D30dNKht8
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Corals, sturgeon and other aquatic creatures harbour signs of infection by influenza and its distant relatives. The influenza virus might have started in fish. Researchers trawling genetic databases have discovered a distant relative of influenza viruses — which are responsible for seasonal flu, not to mention the avian flu roiling the globe — in sturgeon1. The authors also found that the wider virus family that includes influenza probably originated hundreds of millions of years ago in primordial aquatic animals that evolved well before the first fish. Viruses in this group seem to be especially adept at jumping between hosts, says Mary Petrone, a virologist at the University of Sydney, Australia, who co-authored the preprint describing the findings. Knowing about ancient host jumps could help scientists identify viruses with the potential to spark new human epidemics. The study was posted on 16 Feburary to the preprint server bioRxiv and has not yet been peer reviewed. Influenza’s origins story Like many virologists, Petrone spent the first couple years of the pandemic intensively studying SARS-CoV-2. But when she moved to Australia to do postdoctoral research, Petrone wanted to steer clear of human infections and spend time in one of the country’s most famous ecosystems. “After working on COVID for two years, I thought going to coral reefs to do fieldwork sounded really good,” she says. Corals are part of a phylum called Cnidaria, whose ancestors branched off from other animals around 600 million years ago. Petrone hoped that studying corals could reveal the deeper history of viruses that infect animals — particularly those with RNA genomes. This viral group includes numerous human and animal pathogens. Petrone’s first call was not to a diving shop but to Zoe Richards, a coral-reef researcher at Curtin University in Bentley, Australia, who provided samples of two coral species collected off the coast of Western Australia. Analysis of RNA collected from the corals found evidence of infection with viruses that belong to a grouping called Articulavirales, which includes influenza’s family of viruses and a group called Quaranjaviruses. The latter group’s members circulate in ticks and occasionally spill over into humans, birds and other vertebrates. The new analysis suggests that coral-infecting viruses are part of an ancient viral family that probably emerged around 600 million years ago, and later gave rise to other members of Articulavirales, including influenza and Quaranjaviruses. Secrets of the hagfish The discovery got Petrone wondering whether influenza viruses might also have been born at sea. There was already some evidence for this. In 2018, researchers identified a distant relative of influenza in hagfish2. These slimy, jawless creatures descended from an early lineage of vertebrates, and the study’s authors hinted that influenza evolved alongside vertebrates. Searching genetic databases, Petrone found influenza-related RNA sequences in samples from Siberian sturgeon (Acipenser baerii). Sturgeon are jawed vertebrates, more closely related to humans than hagfish are. But the sturgeon virus had branched off from the main influenza family tree before any other known influenza virus, including the hagfish virus. The discovery of the two early lineages of influenza suggest that influenza probably infected aquatic animals, including fish, before moving onto land, says Petrone. But it’s not clear whether influenza moved onto land with early terrestrial vertebrates, or jumped from sea to land more recently. To determine this, researchers will need to look for relatives of influenza in more animals and gain a better understand how the virus spreads between host species, researchers say. Born at sea Jie Cui, an evolutionary virologist at the Pasteur Institute of Shanghai in China, agrees that influenza and its wider family probably emerged from the sea. In 2021, his team analysed deep-sea lobster genomes and identified viruses that are part of influenza’s wider group3. “There is great untapped viral diversity in aquatic environments,” he says. Robert Gifford, an evolutionary virologist at the University of Glasgow, UK, says it would be surprising to find a major group of viruses that didn’t arise in aquatic environments because of the ancient nature of marine life. “The study provides compelling evidence that influenza viruses have an aquatic origin.” Identifying ancient host jumps could also help researchers gauge the risk that certain viruses pose to humans, researchers say. Petrone’s team found signs that Quaranjaviruses that infect ticks might have jumped to the creatures after first circulating in crustaceans. Uncovering such jumps shows that the study of aquatic viruses “can help us to better understand the historic emergence and evolution of viruses with zoonotic potential”, adds Chantal Vogels, an arbovirologist at the Yale School of Public Health in New Haven, Connecticut. Gifford agrees that studies such as Petrone’s could help to identify viruses that have the capacity to spark epidemics in humans and other animals. But he cautions that conclusions about ancient host jumps can change as more of the viral family tree gets filled in, reshuffling relationships. Cited research available in bioRxiv (Feb. 16, 2023): https://doi.org/10.1101/2023.02.15.528772
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The geographic and evolutionary origins of the SARS-CoV-2 Omicron variant (BA.1), which was first detected mid-November 2021 in Southern Africa, remain unknown. We tested 13,097 COVID-19 patients sampled between mid-2021 to early 2022 from 22 African countries for BA.1 by real-time RT-PCR. By November-December 2021, BA.1 had replaced the Delta variant in all African sub-regions following a South-North gradient, with a peak Rt of 4.1. Polymerase chain reaction and near-full genome sequencing data revealed genetically diverse Omicron ancestors already existed across Africa by August 2021. Mutations, altering viral tropism, replication and immune escape, gradually accumulated in the spike gene. Omicron ancestors were therefore present in several African countries months before Omicron dominated transmission. These data also indicate that travel bans are ineffective in the face of undetected and widespread infection. Published in Science (Dec. 1, 2022): https://doi.org/10.1126/science.add8737
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Even as cases rise, genetic analysis suggests that the virus has been silently circulating in people since 2018. When the first monkeypox cases were identified in early May, European health officials were stumped. The virus was not known to spread easily among people, let alone infect dozens — and soon hundreds — of young men. The origins of the outbreak are now becoming clearer. Genetic analysis suggests that although the monkeypox virus is rapidly spreading in the open, it has been silently circulating in people for years. Health officials have already identified two versions of monkeypox among American patients, suggesting at least two separate chains of transmission. Researchers in several countries have found cases with no known source of infection, indicating undetected community spread. And one research team argued last month that monkeypox had already crossed a threshold into sustainable person-to-person transmission. The genetic information available so far indicated that, at some point in the last few years, the virus became better at spreading between people, said Trevor Bedford, an evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle. “Genomic patterns would suggest this occurred around 2018,” Dr. Bedford said. If the virus has adapted to include people as hosts, monkeypox outbreaks could become more frequent and more difficult to contain. That carries the risk that monkeypox could spill over from infected people into animals — most likely rodents — in countries outside Africa, which has struggled with that problem for decades. The virus may persist in infected animals, sporadically triggering new infections in people. “We can also transmit this back to animals that can spread the disease within wildlife and back to humans,” said Sagan Friant, an anthropologist at Pennsylvania State University who has studied human-animal interactions in Nigeria for about 15 years. The longer it takes to contain the virus, the higher the odds that it will find a permanent new home in people or animals, Dr. Friant said. As of Wednesday, the United States had identified 156 cases in 23 states and the District of Columbia. The global toll has surpassed 3,400 confirmed cases, and another 3,500 cases are being evaluated, tripling the numbers from two weeks ago. In Africa, eight countries had reported more than 1,500 suspected cases and 72 deaths as of June 10, most of which were in the Democratic Republic of Congo. Monkeypox is a large double-stranded DNA virus, about seven times as large as the coronavirus. DNA-based viruses can correct their own errors when they replicate their genetic material. They may collect just one or two mutations per year compared with 20 to 30 mutations for an RNA virus like the coronavirus. But the monkeypox virus seems to have amassed an unexpectedly high number of mutations — nearly 50 compared to a version that circulated in 2018, according to preliminary analyses. Of the 47 mutations identified in one analysis, 42 carry the distinct signature of an enzyme called Apobec3. This enzyme, first discovered by researchers studying H.I.V., is a so-called host defense factor — an immune-system weapon that animals and people use to disarm viruses like monkeypox. The enzyme essentially forces viruses to make mistakes when they try to replicate, causing them to self-destruct. Mice carry just one version of this enzyme, while humans have seven. The rapid accumulation of mutations, characteristic of the enzyme since 2018, suggests that monkeypox may have switched to people as hosts around then, Dr. Bedford said. It is unclear how the mutations might change the virus. Of 48 mutations identified in Britain, 21 may affect how the disease spreads, its severity and how well it responds to a treatment called tecovirimat, according to the U.K. Health Security Agency. But because mutations introduced by the enzyme Apobec3 are meant to harm the virus, their quantity alone is not worrying, said Michael Malim, a virologist at King’s College London who discovered Apobec3 in 2002. The effect of the mutations is “more likely to be debilitating,” he said. Comparing the current version of the virus with samples from the past few years might help understand how it has evolved, but that information is scarce. Nigeria did not have the ability to sequence genetic material until 2017. Since then, scientists there have been analyzing the sequences from about 50 monkeypox cases, according to Dr. Ifedayo Adetifa, director of the Nigeria Center for Disease Control. But without the specialized equipment or expertise needed for rapid analysis, the scientists have not yet completed their work, he said. Although the researchers have fielded several requests for the data from outside Nigeria, Dr. Adetifa said they would wait to publish their work to prevent teams with more resources from outcompeting them and grabbing credit. “I’m all for open data sharing and all of that,” he said. “Question is, who benefits?” Some experts have cautioned for years that the eradication of smallpox in 1980 left the world vulnerable to the broader family of poxviruses and raised the odds of monkeypox evolving into a successful human pathogen. In West Africa, the incidence of monkeypox has increased at least twentyfold since 1986. In African countries generally, Dr. Adetifa said, “we suspect some underreporting because there’s been relatively low awareness and maybe low perceived risk of monkeypox.” Nigeria is stepping up its surveillance of monkeypox, and case numbers may rise as more people become aware of the virus, he added. Although monkeypox has a distinctive rash that appears on the palms of the hands and soles of the feet, it is frequently confused with chickenpox. Many men in the current outbreak have lesions on their genitalia, but those can be mistaken for sexually transmitted infections such as syphilis, gonorrhea and chlamydia. Researchers in Italy and Germany have reported finding monkeypox DNA in semen, but it is unclear if the virus spreads that way or is merely present in semen and vaginal secretions. The spread among young men with genital ulcers was observed at least once before. In 2017, Nigeria recorded 228 suspected cases of monkeypox and confirmed 60. The virus spread primarily among young men who had genital ulcers. Britain’s experience indicates how complicated it can be to trace contacts of a virus that may be sexually transmitted, especially in cases where infected people have had multiple anonymous partners. In an initial analysis of a subset of cases, officials said they were able to obtain names for fewer than one-third of the 78 reported sexual contacts. Many cases in Africa have been traced back to contact with wild animals or the use of animal products for medicinal or cultural practices. As deforestation and urbanization drive people and animals into closer quarters, more viruses may make the jump to human hosts. Monkeypox is most likely to leap to people from rodents. There are some 2,000 species of rodents worldwide, composing 40 percent of all mammalian species. The African rope squirrel is a leading candidate as the primary reservoir for monkeypox, but there are other contenders, including striped mice and dormice, giant pouched rats, rusty-nosed rats and brush-tailed porcupines. In a 2003 outbreak in the United States, a shipment of Gambian pouched rats imported from Africa transmitted monkeypox to prairie dogs, which then infected 71 Americans. But officials did not find signs of the virus in animals in the United States once the spate of cases had ended. There’s no guarantee that luck will hold this time. “These spillovers from other species, and what that means and what the trajectory is — it’s very unpredictable,” Dr. Malim said. “And it’s occurring more and more.”
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Scientist who found archived online files of removed NIH data says recovered information may clarify how coronavirus entered humans. In a world starved for any fresh data to help clarify the origin of the COVID-19 pandemic, a study claiming to have unearthed early sequences of SARS-CoV-2 that were deliberately hidden was bound to ignite a sizzling debate. The unreviewed paper, by evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Research Center, asserts that a team of Chinese researchers sampled viruses from some of the earliest COVID-19 patients in Wuhan, China, posted the viral sequences to a widely used U.S. database, and then a few months later had the genetic information removed to “obscure their existence.” To some scientists, the claims reinforce suspicions that China has something to hide about the origins of the pandemic. But critics of the preprint, posted yesterday on bioRxiv, say Bloom’s detective work is much ado about nothing, because the Chinese scientists later published the viral information in a different form, and the recovered sequences add little to what’s known about SARS-CoV-2’s origins. The sequences, Bloom says, do support other evidence that the pandemic did not originate in Wuhan’s Huanan Seafood Market, where SARS-CoV-2 initially came to light. Chinese health officials on 31 December 2019 tied the market to an outbreak of an “unexplained pneumonia,” but a month later, it had become clear that many of the earliest cases had no link to the location. The paper highlights three mutations found in SARS-CoV-2 collected from patients linked to the market that are not in the unearthed sequences of the coronavirus or its closest relative, which researchers from the Wuhan Institute of Virology discovered in bats in 2013. Bloom’s more explosive assertion, that the Chinese researchers deleted data, is bound to intensify the debate about whether the virus originally jumped to humans from an unknown animal or somehow leaked from a laboratory. Bloom says he has no bias toward a particular origin hypothesis for SARS-CoV-2, and he agrees that the viral sequences he highlighted are a small piece of a large unfinished puzzle. “I don't think this bolsters either the lab origin or zoonosis hypothesis,” he says. “I think it provides additional evidence that this virus was probably circulating in Wuhan before December, certainly, and that probably, we have a less than complete picture of the sequences of the early viruses.” Bloom, who studies viral evolution, launched his study after a controversial report on the pandemic’s origin issued in March by a joint commission of Chinese and foreign researchers organized by the World Health Organization (WHO). Bloom helped organize a much discussed letter, co-signed by 17 other scientists, that criticized the WHO report for deeming it “extremely unlikely” that SARS-CoV-2 escaped from a laboratory. In the letter, published on 14 May in Science, the authors argued for “a dispassionate science-based discourse on this difficult but important issue.” The WHO report relied heavily on sequences of SARS-CoV-2 found in COVID-19 patients tied to the market, Bloom notes. “I was just going through and trying to repeat a number of the analyses in the joint WHO-China report,” Bloom says. This led him to a study that listed all SARS-CoV-2 sequences submitted before 31 March 2020 to the Sequence Read Archive (SRA), a database overseen by the National Center for Biotechnology Information, a division of the U.S. National Institutes of Health (NIH). But when he checked SRA for one of the listed projects, he couldn’t find its sequences. Googling some of the project’s information, he found another study, led by Ming Wang from Wuhan University’s Renmin Hospital, that was posted as a preprint on 6 March on medRxiv, and later published, on 24 June, in Small, a journal more focused on materials and chemistry than virology. That paper lists some of the earliest Wuhan COVID-19 patients and the specific mutations in their viruses, but doesn’t give the full sequence data. Further internet sleuthing led Bloom to discover that SRA backs up its information in Google’s Cloud platform, and a search there turned up files containing some of the earlier data submissions from Wang's team. The paper in Small makes no mention of any corrections to viral sequences that might explain why they were removed from SRA, which led Bloom to conclude in his preprint that “the trusting structures of science have been abused to obscure sequences relevant to the early spread of SARS-CoV-2 in Wuhan.” Bloom asserts that because the deleted sequences lack the three mutations seen in the SARS-CoV-2 from the seafood market, the viruses Wang’s team found more likely represent a progenitor. But the sequence of that bat virus found in 2013 differs from SARS-CoV-2 by about 1100 nucleotides, which means decades must have passed before it evolved into the pandemic coronavirus—and other species may well have been infected with the bat virus before it made the final jump into people. This great difference in sequences, says evolutionary biologist Andrew Rambaut at the University of Edinburgh, means researchers cannot use a few mutations like the ones Bloom highlights to look back in time to see the “roots” of the family tree of SARS-CoV-2 tree. Bloom says he contacted the Chinese researchers to ask why they removed the SRA data, but they did not reply. (Science also received no reply after emailing the lead authors.) NIH issued a statement today saying it removed the sequences at the request of the submitting investigator, who the agency says holds the rights to the data. The scientist “indicated the sequence information had been updated, was being submitted to another database, and wanted the data removed from SRA to avoid version control issues,” NIH said. (Bloom says he cannot find the sequences in any other virology database he knows.) Researchers are sharply divided about the value of Bloom’s resurrection of the SRA data. “This is a creative and rigorous approach to investigating the provenance of SARS-CoV-2,” says Ian Lipkin, a microbiologist at Columbia University’s Mailman School of Public Health. “The two take-home points are that the virus was circulating before the outbreak linked to the Wuhan seafood market and that there may have been active suppression of epidemiological and sequence data needed to track its origin.” Leaving aside the meaning of the sequences Bloom found, the demonstration that researchers can potentially find “new” data in the cloud is an exciting advance, adds Sudhir Kumar, who does genomics research at Temple University and has published his own analysis of early SARS-CoV-2 sequences, “Many people feel that there is a lot more Chinese data out there, and they don't have access to it,” he says. Others are underwhelmed. “Jesse is resurfacing info that’s been online for over a year and claiming it proves a cover-up,” says Stephen Goldstein, an evolutionary virologist at the University of Utah. “I don’t understand [his reasoning].” The Small paper is simply a good study that “unfortunately flew below the radar,” he adds. Rambaut notes that the Chinese researchers submitted their Small paper before requesting SRA remove the data. “The idea that the group was trying to hide something is farcical,” Rambaut says. “If they were covering something [up] they surely would have not submitted the paper. … I don't like the insinuations about malfeasance where [Bloom] has zero knowledge of the reasons the authors of the paper had for removing their data.” A member of the WHO origin commission, Marion Koopmans from the Erasmus University Medical Center, notes that its report stresses the need to find more data about the earliest viruses in circulation. “It’s good to see additional data, but I’m not sure what point this makes,” Koopmans says, adding that the preprint’s accusations could harm future collaborations on origin studies with Chinese researchers. “The tone of the intro is in my view rather suggestive and I wish science would stay away from this.” Bloom acknowledges that researchers can piece together the coronavirus sequences from the data found in the Small paper, but he says that’s not the way most in the field conduct evolutionary analyses of SARS-CoV-2. “No one knew about these sequences because the way that people find sequences is to go to the sequence databases and download the sequences and look at them,” Bloom says. Stepping into the divisive discussion of SARS-CoV-2’s origin comes at a price, he acknowledges. “So many people have agendas and preconceived notions on this topic that if you open your mouth on the topic, someone's going to take what you've said to support or reject some particular narrative,” he says. “So the choices are either not to say anything at all, which I don't think is useful or productive, or just to try to draw the conclusions you can and make it as transparent as possible. No matter how much people like [my new study] or don't like it, or agree with the interpretation or disagree with the interpretation, they can at least go download it and repeat it themselves.” Published in Science (June 23, 2021): https://doi.org/10.1126/science.abk1383 Preprint of the research cited available in bioRxiv (June 22, 2021): https://doi.org/10.1101/2021.06.18.449051
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The second notable feature of SARS-CoV-2 is a predicted polybasic cleavage site (RRAR) in the spike protein at the junction of S1 and S2, the two subunits of the spike protein (Figure 1b)8,9. In addition to two basic arginines and an alanine at the cleavage site, a leading proline is also inserted; thus, the fully inserted sequence is PRRA (Figure 1b). The strong turn created by the proline insertion is predicted to result in the addition of O-linked glycans to S673, T678, and S686 that flank the polybasic cleavage site. A polybasic cleavage site has not previously been observed in related lineage B betacoronaviruses and is a unique feature of SARS-CoV-2. Some human betacoronaviruses, including HCoV-HKU1 (lineage A), have polybasic cleavage sites, as well as predicted O-linked glycans near the S1/S2 cleavage site. While the functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, experiments with SARS-CoV have shown that engineering such a site at the S1/S2 junction enhances cell–cell fusion but does not affect virus entry10. Polybasic cleavage sites allow effective cleavage by furin and other proteases, and can be acquired at the junction of the two subunits of the haemagglutinin (HA) protein of avian influenza viruses in conditions that select for rapid virus replication and transmission (e.g. highly dense chicken populations). HA serves a similar function in cell-cell fusion and viral entry as the coronavirus S protein. Acquisition of a polybasic cleavage site in HA, by either insertion or recombination, converts low pathogenicity avian influenza viruses into highly pathogenic forms11-13. The acquisition of polybasic cleavage sites by the influenza virus HA has also been observed after repeated forced passage in cell culture or through animals14,15. Similarly, an avirulent isolate of Newcastle Disease virus became highly pathogenic during serial passage in chickens by incremental acquisition of a polybasic cleavage site at the junction of its fusion protein subunits.... ...It is improbable that SARS-CoV-2 emerged through laboratory manipulation of an existing SARS-related coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for human ACE2 receptor binding with an efficient binding solution different to that which would have been predicted. Further, if genetic manipulation had been performed, one would expect that one of the several reverse genetic systems available for betacoronaviruses would have been used. However, this is not the case as the genetic data shows that SARS-CoV-2 is not derived from any previously used virus backbone17. Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in a non-human animal host prior to zoonotic transfer, and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage in culture could have given rise to the same observed features... Mandarin version of the article available at: http://virological.org/uploads/short-url/dHpDmgjWKLNlBztUWteEJZq4Pvw.pdf
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