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Abstract
Bats are presumed reservoirs of diverse coronaviruses (CoVs) including progenitors
of Severe Acute Respiratory Syndrome (SARS)-CoV and SARS-CoV-2, the causative agent
of COVID-19. However, the evolution and diversification of these coronaviruses remains
poorly understood. Here we use a Bayesian statistical framework and a large sequence
data set from bat-CoVs (including 630 novel CoV sequences) in China to study their
macroevolution, cross-species transmission and dispersal. We find that host-switching
occurs more frequently and across more distantly related host taxa in alpha- than
beta-CoVs, and is more highly constrained by phylogenetic distance for beta-CoVs.
We show that inter-family and -genus switching is most common in Rhinolophidae and
the genus
Rhinolophus. Our analyses identify the host taxa and geographic regions that define hotspots
of CoV evolutionary diversity in China that could help target bat-CoV discovery for
proactive zoonotic disease surveillance. Finally, we present a phylogenetic analysis
suggesting a likely origin for SARS-CoV-2 in
Rhinolophus spp. bats.
Abstract
Bats are a likely reservoir of zoonotic coronaviruses (CoVs). Here, analyzing bat
CoV sequences in China, the authors find that alpha-CoVs have switched hosts more
frequently than betaCoVs, identify a bat family and genus that are highly involved
in host-switching, and define hotspots of CoV evolutionary diversity.
Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
The severe acute respiratory syndrome (SARS) has recently been identified as a new clinical entity. SARS is thought to be caused by an unknown infectious agent. Clinical specimens from patients with SARS were searched for unknown viruses with the use of cell cultures and molecular techniques. A novel coronavirus was identified in patients with SARS. The virus was isolated in cell culture, and a sequence 300 nucleotides in length was obtained by a polymerase-chain-reaction (PCR)-based random-amplification procedure. Genetic characterization indicated that the virus is only distantly related to known coronaviruses (identical in 50 to 60 percent of the nucleotide sequence). On the basis of the obtained sequence, conventional and real-time PCR assays for specific and sensitive detection of the novel virus were established. Virus was detected in a variety of clinical specimens from patients with SARS but not in controls. High concentrations of viral RNA of up to 100 million molecules per milliliter were found in sputum. Viral RNA was also detected at extremely low concentrations in plasma during the acute phase and in feces during the late convalescent phase. Infected patients showed seroconversion on the Vero cells in which the virus was isolated. The novel coronavirus might have a role in causing SARS. Copyright 2003 Massachusetts Medical Society
[1
]GRID grid.420826.a, ISNI 0000 0004 0409 4702, EcoHealth Alliance, ; New York, USA
[2
]GRID grid.9227.e, ISNI 0000000119573309, Key Laboratory of Special Pathogens And Biosafety, Wuhan Institute of Virology, Center
for Biosafety Mega-Science, , Chinese Academy of Sciences, ; Wuhan, China
[3
]GRID grid.464309.c, ISNI 0000 0004 6431 5677, Guangdong Institute of Applied Biological Resources, , Guangdong Academy of Sciences, ; Guangzhou, China
[4
]GRID grid.1003.2, ISNI 0000 0000 9320 7537, School of Veterinary Science, , The University of Queensland, ; Brisbane, QLD Australia
[5
]GRID grid.428397.3, ISNI 0000 0004 0385 0924, Programme in Emerging Infectious Diseases, , Duke-NUS Medical School, ; Singapore, Singapore
[6
]GRID grid.269823.4, ISNI 0000 0001 2164 6888, Present Address: Wildlife Conservation Society, Viet Nam Country Program, Ha Noi,
Viet Nam; Wildlife Conservation Society, , Health Program, ; Bronx, NY USA
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History
Date
received
: 6
October
2019
Date
accepted
: 6
July
2020
Funding
Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and
Infectious Diseases (NIAID);
Award ID: R01AI110964
Award Recipient
:
Peter Daszak
Funded by: FundRef https://doi.org/10.13039/100000200, United States Agency for International Development (U.S. Agency for International
Development);