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No credible evidence supporting claims of the laboratory engineering of SARS-CoV-2

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Emerging Microbes & Infections
Authors:
Shan-Lu Liu
Shan-Lu Liu
Shan-Lu Liu
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Linda J. Saif
Linda J. Saif
Linda J. Saif
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Susan R. Weiss
Susan R. Weiss
Susan R. Weiss
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Lishan Su
Lishan Su
Lishan Su
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No credible evidence supporting claims of the
laboratory engineering of SARS-CoV-2
Shan-Lu Liu, Linda J. Saif, Susan R. Weiss & Lishan Su
To cite this article: Shan-Lu Liu, Linda J. Saif, Susan R. Weiss & Lishan Su (2020) No credible
evidence supporting claims of the laboratory engineering of SARS-CoV-2, Emerging Microbes &
Infections, 9:1, 505-507, DOI: 10.1080/22221751.2020.1733440
To link to this article: https://doi.org/10.1080/22221751.2020.1733440
© 2020 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group, on behalf of Shanghai Shangyixun
Cultural Communication Co., Ltd
Published online: 26 Feb 2020.
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COMMENTARY
No credible evidence supporting claims of the laboratory engineering of
SARS-CoV-2
Shan-Lu Liu
a,b,c,d
, Linda J. Saif
d,e
, Susan R. Weiss
f
and Lishan Su
g
a
Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA;
b
Department of Veterinary Biosciences, The Ohio State
University, Columbus, OH, USA;
c
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA;
d
Viruses
and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA;
e
Food Animal Health
Research Program, Ohio Agricultural Research and Development Center, CFAES, Department of Veterinary Preventive Medicine, The Ohio
State University, Wooster, OH, USA;
f
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia,
PA, USA;
g
Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel
Hill, Chapel Hill, NC, USA
ARTICLE HISTORY Received 13 February 2020; Accepted 13 February 2020
The emergence and outbreak of a newly discovered
acute respiratory disease in Wuhan, China, has affected
greater than 40,000 people, and killed more than 1,000
as of Feb. 10, 2020. A new human coronavirus, SARS-
CoV-2, was quickly identified, and the associated dis-
ease is now referred to as coronavirus disease discov-
ered in 2019 (COVID-19) (https://globalbiodefense.
com/novel-coronavirus-covid-19-portal/).
According to what has been reported [1–3],
COVID-2019 seems to have similar clinical manifes-
tations to that of the severe acute respiratory syndrome
(SARS) caused by SARS-CoV. The SARS-CoV-2 gen-
ome sequence also has ∼80% identity with SARS-
CoV, but it is most similar to some bat beta-corona-
viruses, with the highest being >96% identity [4,5].
Currently, there are speculations, rumours and con-
spiracy theories that SARS-CoV-2 is of laboratory ori-
gin. Some people have alleged that the human SARS-
CoV-2 was leaked directly from a laboratory in
Wuhan where a bat CoV (RaTG13) was recently
reported, which shared ∼96% homology with the
SARS-CoV-2 [4]. However, as we know, the human
SARS-CoV and intermediate host palm civet SARS-
like CoV shared 99.8% homology, with a total of 202
single-nucleotide (nt) variations (SNVs) identified
across the genome [6]. Given that there are greater
than 1,100 nt differences between the human SARS-
CoV-2 and the bat RaTG13-CoV [4], which are distrib-
uted throughout the genome in a naturally occurring
pattern following the evolutionary characteristics typi-
cal of CoVs, it is highly unlikely that RaTG13 CoV is
the immediate source of SARS-CoV-2. The absence
of a logical targeted pattern in the new viral sequences
and a close relative in a wildlife species (bats) are the
most revealing signs that SARS-CoV-2 evolved by
natural evolution. A search for an intermediate animal
host between bats and humans is needed to identify
animal CoVs more closely related to human SARS-
CoV-2. There is speculation that pangolins might
carry CoVs closely related to SARS-CoV-2, but the
data to substantiate this is not yet published (https://
www.nature.com/articles/d41586-020-00364-2).
Another claim in Chinese social media points to a
Nature Medicine paper published in 2015 [7], which
reports the construction of a chimeric CoV with a
bat CoV S gene (SHC014) in the backbone of a SARS
CoV that has adapted to infect mice (MA15) and is
capable of infecting human cells [8]. However, this
claim lacks any scientific basis and must be discounted
because of significant divergence in the genetic
sequence of this construct with the new SARS-CoV-2
(>5,000 nucleotides).
The mouse-adapted SARS virus (MA15) [9] was
generated by serial passage of an infectious wildtype
SARS CoV clone in the respiratory tract of BALB/c
mice. After 15 passages in mice, the SARS-CoV gained
elevated replication and lung pathogenesis in aged mice
(hence M15), due to six coding genetic mutations
associated with mouse adaptation. It is likely that
MA15 is highly attenuated to replicate in human cells
or patients due to the mouse adaptation.
It was proposed that the S gene from bat-derived
CoV, unlike that from human patients- or civets-
derived viruses, was unable to use human ACE2 as a
receptor for entry into human cells [10,11]. Civets
were proposed to be an intermediate host of the bat-
CoVs, capable of spreading SARS CoV to humans
[6,12]. However, in 2013 several novel bat corona-
viruses were isolated from Chinese horseshoe bats
and the bat SARS-like or SL-CoV-WIV1 was able to
use ACE2 from humans, civets and Chinese horseshoe
bats for entry [8]. Combined with evolutionary
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONTACT Shan-Lu Liu Liu.6244@osu.edu; Lishan Su lsu@med.unc.edu
Emerging Microbes & Infections
2020, VOL. 9
https://doi.org/10.1080/22221751.2020.1733440
evidence that the bat ACE2 gene has been positively
selected at the same contact sites as the human ACE2
gene for interacting with SARS CoV [13], it was pro-
posed that an intermediate host may not be necessary
and that some bat SL-CoVs may be able to directly
infect human hosts. To directly address this possibility,
the exact S gene from bat coronavirus SL-SHC014 was
synthesized and used to generate a chimeric virus in the
mouse adapted MA15 SARS-CoV backbone. The resul-
tant SL-SHC014-MA15 virus could indeed efficiently
use human ACE2 and replicate in primary human
airway cells to similar titres as epidemic strains of
SARS-CoV. While SL-SHC014-MA15 can replicate
efficiently in young and aged mouse lungs, infection
was attenuated, and less virus antigen was present in
the airway epithelium as compared to SARS MA15,
which causes lethal outcomes in aged mice [7].
Due to the elevated pathogenic activity of the
SHC014-MA15 chimeric virus relative to MA15 chi-
meric virus with the original human SARS S gene in
mice, such experiments with SL-SHC014-MA15 chi-
meric virus were later restricted as gain of function
(GOF) studies under the US government-mandated
pause policy (https://www.nih.gov/about-nih/who-we-
are/nih-director/statements/nih-lifts-funding-pause-
gain-function-research). The current COVID-2019
epidemic has restarted the debate over the risks of con-
structing such viruses that could have pandemic poten-
tial, irrespective of the finding that these bat CoVs
already exist in nature. Regardless, upon careful phylo-
genetic analyses by multiple international groups
[5,14], the SARS-CoV-2 is undoubtedly distinct from
SL-SHC014-MA15, with >6,000 nucleotide differences
across the whole genome. Therefore, once again there
is no credible evidence to support the claim that the
SARS-CoV-2 is derived from the chimeric SL-
SHC014-MA15 virus.
There are also rumours that the SARS-CoV-2 was
artificially, or intentionally, made by humans in the
lab, and this is highlighted in one manuscript sub-
mitted to BioRxiv (a manuscript sharing site prior to
any peer review), claiming that SARS-CoV-2 has
HIV sequence in it and was thus likely generated in
the laboratory. In a rebuttal paper led by an HIV-1 vir-
ologist Dr. Feng Gao, they used careful bioinformatics
analyses to demonstrate that the original claim of mul-
tiple HIV insertions into the SARS-CoV-2 is not HIV-1
specific but random [15]. Because of the many con-
cerns raised by the international community, the
authors who made the initial claim have already with-
drawn this report.
Evolution is stepwise and accrues mutations gradu-
ally over time, whereas synthetic constructs would typi-
cally use a known backbone and introduce logical or
targeted changes instead of the randomly occurring
mutations that are present in naturally isolated viruses
such as bat CoV RaTG13. In our view, there is
currently no credible evidence to support the claim
that SARS-CoV-2 originated from a laboratory-engin-
eered CoV. It is more likely that SARS-CoV-2 is a
recombinant CoV generated in nature between a bat
CoV and another coronavirus in an intermediate ani-
mal host. More studies are needed to explore this possi-
bility and resolve the natural origin of SARS-CoV-2.
We should emphasize that, although SARS-CoV-2
shows no evidence of laboratory origin, viruses with
such great public health threats must be handled prop-
erly in the laboratory and also properly regulated by the
scientific community and governments.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Susan R. Weiss http://orcid.org/0000-0002-8155-4528
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Full-text available
  • Feb 2020
Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 10⁹/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.
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A pneumonia outbreak associated with a new coronavirus of probable bat origin
Article
Full-text available
  • Mar 2020
  • NATURE
Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1–4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a novel coronavirus (2019-nCoV) which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started from 12 December 2019, has caused 2,050 laboratory-confirmed infections with 56 fatal cases by 26 January 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The 2019-nCoV virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.
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A new coronavirus associated with human respiratory disease in China
Article
Full-text available
  • Mar 2020
  • NATURE
Emerging infectious diseases, such as SARS and Zika, present a major threat to public health1–3. Despite intense research efforts, how, when and where new diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city Wuhan, Hubei province, China. Up to 25th of January 2020, at least 1,975 cases have been reported since the first patient was hospitalized on the 12th of December 2019. Epidemiological investigation suggested that the outbreak was associated with a seafood market in Wuhan. We studied one patient who was a worker at the market, and who was admitted to Wuhan Central Hospital on 26th of December 2019 experiencing a severe respiratory syndrome including fever, dizziness and cough. Metagenomic RNA sequencing4 of a bronchoalveolar lavage fluid sample identified a novel RNA virus from the family Coronaviridae, designed here as WH-Human-1 coronavirus. Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) previously sampled from bats in China. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans.
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A Novel Coronavirus from Patients with Pneumonia in China, 2019
Article
Full-text available
  • Jan 2020
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
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A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence
Article
Full-text available
  • Nov 2015
  • NAT MED
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.
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Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor
Article
Full-text available
  • Oct 2013
  • NATURE
The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.
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Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study
Article
  • Jan 2020
Background: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding: National Key R&D Program of China.
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