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1.
J Proteome Res ; 19(4): 1351-1360, 2020 04 03.
Article in English | MEDLINE | ID: covidwho-688546

ABSTRACT

As the infection of 2019-nCoV coronavirus is quickly developing into a global pneumonia epidemic, the careful analysis of its transmission and cellular mechanisms is sorely needed. In this Communication, we first analyzed two recent studies that concluded that snakes are the intermediate hosts of 2019-nCoV and that the 2019-nCoV spike protein insertions share a unique similarity to HIV-1. However, the reimplementation of the analyses, built on larger scale data sets using state-of-the-art bioinformatics methods and databases, presents clear evidence that rebuts these conclusions. Next, using metagenomic samples from Manis javanica, we assembled a draft genome of the 2019-nCoV-like coronavirus, which shows 73% coverage and 91% sequence identity to the 2019-nCoV genome. In particular, the alignments of the spike surface glycoprotein receptor binding domain revealed four times more variations in the bat coronavirus RaTG13 than in the Manis coronavirus compared with 2019-nCoV, suggesting the pangolin as a missing link in the transmission of 2019-nCoV from bats to human.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Genome, Viral/genetics , Host-Pathogen Interactions , Models, Molecular , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Eutheria/virology , HIV-1/genetics , Humans , Metagenome , Pandemics , Protein Structure, Tertiary , Sequence Alignment , Sequence Analysis, Protein , Snakes/virology
2.
Adv Virus Res ; 107: 383-416, 2020.
Article in English | MEDLINE | ID: covidwho-679455

ABSTRACT

Since the end of 2019, the global COVID-19 outbreak has once again made coronaviruses a hot topic. Vaccines are hoped to be an effective way to stop the spread of the virus. However, there are no clinically approved vaccines available for coronavirus infections. Reverse genetics technology can realize the operation of RNA virus genomes at the DNA level and provide new ideas and strategies for the development of new vaccines. In this review, we systematically describe the role of reverse genetics technology in studying the effects of coronavirus proteins on viral virulence and innate immunity, cell and tissue tropism and antiviral drug screening. An efficient reverse genetics platform is useful for obtaining the ideal attenuated strain to prepare an attenuated live vaccine.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Vaccines, Synthetic/immunology , Viral Proteins/genetics , Viral Proteins/immunology , Viral Vaccines/immunology , Coronavirus Infections/immunology , Genome, Viral/genetics , Humans , Pneumonia, Viral/immunology , RNA, Viral/genetics , Reverse Genetics/methods
3.
Nat Commun ; 11(1): 3496, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640239

ABSTRACT

SARS-CoV-2, a coronavirus that emerged in late 2019, has spread rapidly worldwide, and information about the modes of transmission of SARS-CoV-2 among humans is critical to apply appropriate infection control measures and to slow its spread. Here we show that SARS-CoV-2 is transmitted efficiently via direct contact and via the air (via respiratory droplets and/or aerosols) between ferrets, 1 to 3 days and 3 to 7 days after exposure respectively. The pattern of virus shedding in the direct contact and indirect recipient ferrets is similar to that of the inoculated ferrets and infectious virus is isolated from all positive animals, showing that ferrets are productively infected via either route. This study provides experimental evidence of robust transmission of SARS-CoV-2 via the air, supporting the implementation of community-level social distancing measures currently applied in many countries in the world and informing decisions on infection control measures in healthcare settings.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Animals , Antibodies, Viral/blood , Betacoronavirus/genetics , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Disease Models, Animal , Ferrets , Genome, Viral/genetics , Humans , Pandemics , Rectum/virology , Respiratory System/virology , Sequence Analysis, RNA , Virus Shedding
4.
Euro Surveill ; 25(26)2020 07.
Article in English | MEDLINE | ID: covidwho-639489

ABSTRACT

Following SARS-CoV-2 emergence in China, a specific surveillance was implemented in France. Phylogenetic analysis of sequences retrieved through this surveillance suggests that detected initial introductions, involving non-clade G viruses, did not seed local transmission. Nevertheless, identification of clade G variants subsequently circulating in the country, with the earliest from a patient who neither travelled to risk areas nor had contact with travellers, suggests that SARS-CoV-2 might have been present before the first recorded local cases.


Subject(s)
Coronavirus Infections/genetics , Coronavirus/genetics , Disease Outbreaks/prevention & control , Sentinel Surveillance , Betacoronavirus , Coronavirus/classification , Coronavirus/isolation & purification , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , France/epidemiology , Genome, Viral/genetics , Humans , Pandemics/prevention & control , Phylogeny , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis , Viral Proteins/genetics
5.
mSphere ; 5(3)2020 06 24.
Article in English | MEDLINE | ID: covidwho-612518

ABSTRACT

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a data set of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean of 5.5 to 9.5 nucleotide differences from each other, consistent with a midrange coronavirus substitution rate of 3 × 10-4 substitutions/site/year. Almost one-half of sequence changes were C→U transitions, with an 8-fold base frequency normalized directional asymmetry between C→U and U→C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV, Middle East respiratory syndrome [MERS]-CoV), and decreasing ratios were observed in other human coronaviruses (HCoV-NL63, -OC43, -229E, and -HKU1) proportionate to their increasing divergence. C→U transitions underpinned almost one-half of the amino acid differences between SARS-CoV-2 variants and occurred preferentially in both 5' U/A and 3' U/A flanking sequence contexts comparable to favored motifs of human APOBEC3 proteins. Marked base asymmetries observed in nonpandemic human coronaviruses (U ≫ A > G ≫ C) and low G+C contents may represent long-term effects of prolonged C→U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short- and long-term evolution. Repeated cycles of mutation and reversion in favored mutational hot spots and the widespread occurrence of amino acid changes with no adaptive value for the virus represent a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks and are not incorporated by standard models used in molecular epidemiology investigations.IMPORTANCE The wealth of accurately curated sequence data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its long genome, and its low substitution rate provides a relatively blank canvas with which to investigate effects of mutational and editing processes imposed by the host cell. The finding that a large proportion of sequence change in SARS-CoV-2 in the initial months of the pandemic comprised C→U mutations in a host APOBEC-like context provides evidence for a potent host-driven antiviral editing mechanism against coronaviruses more often associated with antiretroviral defense. In evolutionary terms, the contribution of biased, convergent, and context-dependent mutations to sequence change in SARS-CoV-2 is substantial, and these processes are not incorporated by standard models used in molecular epidemiology investigations.


Subject(s)
Betacoronavirus/genetics , Cytosine/analysis , Genome, Viral/genetics , Polymorphism, Single Nucleotide/genetics , Uracil/analysis , Base Composition/genetics , Base Sequence/genetics , Coronavirus Infections/pathology , Cytidine Deaminase/genetics , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Pandemics , Pneumonia, Viral/pathology , SARS Virus/genetics
6.
J Pak Med Assoc ; 70(Suppl 3)(5): S38-S43, 2020 May.
Article in English | MEDLINE | ID: covidwho-609354

ABSTRACT

COVID-19 has taken the world by storm in the ongoing pandemic. The virus responsible for COVID-19 disease is 'severe acute respiratory syndrome coronavirus-2' SARS-CoV-2, an enveloped RNA beta-coronavirus from the family Coronaviridae. There have been similar beta-coronavirus disease outbreaks previously: Severe acute respiratory syndrome (SARS - 2002) and Middle East respiratory syndrome (MERS - 2012) epidemics. SARS-CoV-2 origins have been traced to bat reservoirs. A virus with a high capacity for mutation, SARS-CoV-2 poses unique challenges both in the current form of disease control and management, while also leaving the door open for future novel diseases and pandemics. An understanding of the virion structure and genomic organisation will help us in understanding their origins and likely course of future evolution. Moreover, novel cost-effective methodologies for genetic surveillance may help in mitigating the emergence of these viral infections in future. In this manuscript, the authors have detailed the unique aspects of the SARS-CoV-2 virus genome and its clinical implications.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Pneumonia, Viral/virology , Animals , Asia , Chiroptera/virology , Coronavirus Infections/transmission , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing , Humans , Mutation/genetics , Mutation Rate , Pandemics , Pneumonia, Viral/transmission , RNA, Viral/genetics , Virion/genetics
7.
Viruses ; 12(6)2020 06 04.
Article in English | MEDLINE | ID: covidwho-593124

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the betacoronavirus family, which causes COVID-19 disease. SARS-CoV-2 pathogenicity in humans leads to increased mortality rates due to alterations of significant pathways, including some resulting in exacerbated inflammatory responses linked to the "cytokine storm" and extensive lung pathology, as well as being linked to a number of comorbidities. Our current study compared five SARS-CoV-2 sequences from different geographical regions to those from SARS, MERS and two cold viruses, OC43 and 229E, to identify the presence of miR-like sequences. We identified seven key miRs, which highlight considerable differences between the SARS-CoV-2 sequences, compared with the other viruses. The level of conservation between the five SARS-CoV-2 sequences was identical but poor compared with the other sequences, with SARS showing the highest degree of conservation. This decrease in similarity could result in reduced levels of transcriptional control, as well as a change in the physiological effect of the virus and associated host-pathogen responses. MERS and the milder symptom viruses showed greater differences and even significant sequence gaps. This divergence away from the SARS-CoV-2 sequences broadly mirrors the phylogenetic relationships obtained from the whole-genome alignments. Therefore, patterns of mutation, occurring during sequence divergence from the longer established human viruses to the more recent ones, may have led to the emergence of sequence motifs that can be related directly to the pathogenicity of SARS-CoV-2. Importantly, we identified 7 key-microRNAs (miRs 8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) with significant links to KEGG pathways linked to viral pathogenicity and host responses. According to Bioproject data (PRJNA615032), SARS-CoV-2 mediated transcriptomic alterations were similar to the target pathways of the selected 7 miRs identified in our study. This mechanism could have considerable significance in determining the symptom spectrum of future potential pandemics. KEGG pathway analysis revealed a number of critical pathways linked to the seven identified miRs that may provide insight into the interplay between the virus and comorbidities. Based on our reported findings, miRNAs may constitute potential and effective therapeutic approaches in COVID-19 and its pathological consequences.


Subject(s)
Betacoronavirus/genetics , Genome, Viral/genetics , MicroRNAs/physiology , Severe Acute Respiratory Syndrome/virology , Signal Transduction/physiology , Base Sequence , Betacoronavirus/pathogenicity , Comorbidity , Computational Biology , Databases, Genetic , Humans , MicroRNAs/genetics , Mutation , Sequence Alignment
8.
Microb Biotechnol ; 13(3): 607-612, 2020 05.
Article in English | MEDLINE | ID: covidwho-589740

ABSTRACT

Another animal to human transmission of a coronavirus occurred in December 2019 on a live animal market in the Chinese city of Wuhan causing an epidemic in China, reaching now different continents. This minireview summarizes the research literature on the virological, clinical and epidemiological aspects of this epidemic published until end of February 2020.


Subject(s)
Betacoronavirus , Coronavirus Infections , Disease Outbreaks , Pandemics , Pneumonia, Viral , Animals , Betacoronavirus/classification , Betacoronavirus/physiology , China , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Pneumonia, Viral/virology
10.
Euro Surveill ; 25(22)2020 Jun.
Article in English | MEDLINE | ID: covidwho-525969

ABSTRACT

We whole-genome sequenced 55 SARS-CoV-2 isolates from Germany to investigate SARS-CoV-2 outbreaks in 2020 in the Heinsberg district and Düsseldorf. While the genetic structure of the Heinsberg outbreak indicates a clonal origin, reflecting superspreading dynamics from mid-February during the carnival season, distinct viral strains were circulating in Düsseldorf in March, reflecting the city's international links. Limited detection of Heinsberg strains in the Düsseldorf area despite geographical proximity may reflect efficient containment and contact-tracing efforts.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Genome, Viral/genetics , Pandemics , Pneumonia, Viral/diagnosis , Whole Genome Sequencing/methods , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Disease Outbreaks , Germany/epidemiology , Humans , Pneumonia, Viral/epidemiology , RNA-Directed DNA Polymerase , Reverse Transcriptase Polymerase Chain Reaction
12.
J Virol ; 94(12)2020 06 01.
Article in English | MEDLINE | ID: covidwho-459315

ABSTRACT

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that recently emerged in China is thought to have a bat origin, as its closest known relative (BatCoV RaTG13) was described previously in horseshoe bats. We analyzed the selective events that accompanied the divergence of SARS-CoV-2 from BatCoV RaTG13. To this end, we applied a population genetics-phylogenetics approach, which leverages within-population variation and divergence from an outgroup. Results indicated that most sites in the viral open reading frames (ORFs) evolved under conditions of strong to moderate purifying selection. The most highly constrained sequences corresponded to some nonstructural proteins (nsps) and to the M protein. Conversely, nsp1 and accessory ORFs, particularly ORF8, had a nonnegligible proportion of codons evolving under conditions of very weak purifying selection or close to selective neutrality. Overall, limited evidence of positive selection was detected. The 6 bona fide positively selected sites were located in the N protein, in ORF8, and in nsp1. A signal of positive selection was also detected in the receptor-binding motif (RBM) of the spike protein but most likely resulted from a recombination event that involved the BatCoV RaTG13 sequence. In line with previous data, we suggest that the common ancestor of SARS-CoV-2 and BatCoV RaTG13 encoded/encodes an RBM similar to that observed in SARS-CoV-2 itself and in some pangolin viruses. It is presently unknown whether the common ancestor still exists and, if so, which animals it infects. Our data, however, indicate that divergence of SARS-CoV-2 from BatCoV RaTG13 was accompanied by limited episodes of positive selection, suggesting that the common ancestor of the two viruses was poised for human infection.IMPORTANCE Coronaviruses are dangerous zoonotic pathogens; in the last 2 decades, three coronaviruses have crossed the species barrier and caused human epidemics. One of these is the recently emerged SARS-CoV-2. We investigated how, since its divergence from a closely related bat virus, natural selection shaped the genome of SARS-CoV-2. We found that distinct coding regions in the SARS-CoV-2 genome evolved under conditions of different degrees of constraint and are consequently more or less prone to tolerate amino acid substitutions. In practical terms, the level of constraint provides indications about which proteins/protein regions are better suited as possible targets for the development of antivirals or vaccines. We also detected limited signals of positive selection in three viral ORFs. However, we warn that, in the absence of knowledge about the chain of events that determined the human spillover, these signals should not be necessarily interpreted as evidence of an adaptation to our species.


Subject(s)
Betacoronavirus/genetics , Evolution, Molecular , Selection, Genetic , Amino Acid Sequence , Animals , Betacoronavirus/classification , Chiroptera/virology , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Models, Molecular , Open Reading Frames/genetics , Pandemics , Phylogeny , Pneumonia, Viral/virology , Viral Proteins/chemistry , Viral Proteins/genetics
13.
Sci Adv ; 6(25): eabb5813, 2020 06.
Article in English | MEDLINE | ID: covidwho-619103

ABSTRACT

The COVID-19 outbreak has become a global health risk, and understanding the response of the host to the SARS-CoV-2 virus will help to combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-infected patients. We identify nucleotide changes that may be signatures of RNA editing: adenosine-to-inosine changes from ADAR deaminases and cytosine-to-uracil changes from APOBEC deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. Our results thus suggest that both APOBECs and ADARs are involved in coronavirus genome editing, a process that may shape the fate of both virus and patient.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/metabolism , Coronavirus Infections/genetics , Host-Pathogen Interactions/genetics , Pneumonia, Viral/genetics , RNA Editing/genetics , Transcriptome , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Base Sequence/genetics , Bronchoalveolar Lavage Fluid/virology , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Mutation Rate , Nucleotides/genetics , Nucleotides/metabolism , Pandemics , Pneumonia, Viral/virology , RNA, Viral/genetics , Virus Replication/genetics
14.
mBio ; 11(3)2020 05 29.
Article in English | MEDLINE | ID: covidwho-432175

ABSTRACT

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was recently identified as the causative agent for the coronavirus disease 2019 (COVID-19) outbreak that has generated a global health crisis. We use a combination of genomic analysis and sensitive profile-based sequence and structure analysis to understand the potential pathogenesis determinants of this virus. As a result, we identify several fast-evolving genomic regions that might be at the interface of virus-host interactions, corresponding to the receptor binding domain of the Spike protein, the three tandem Macro fold domains in ORF1a, and the uncharacterized protein ORF8. Further, we show that ORF8 and several other proteins from alpha- and beta-CoVs belong to novel families of immunoglobulin (Ig) proteins. Among them, ORF8 is distinguished by being rapidly evolving, possessing a unique insert, and having a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncover numerous Ig domain proteins from several unrelated metazoan viruses, which are distinct in sequence and structure but share comparable architectures to those of the CoV Ig domain proteins. Hence, we propose that SARS-CoV-2 ORF8 and other previously unidentified CoV Ig domain proteins fall under the umbrella of a widespread strategy of deployment of Ig domain proteins in animal viruses as pathogenicity factors that modulate host immunity. The rapid evolution of the ORF8 Ig domain proteins points to a potential evolutionary arms race between viruses and hosts, likely arising from immune pressure, and suggests a role in transmission between distinct host species.IMPORTANCE The ongoing COVID-19 pandemic strongly emphasizes the need for a more complete understanding of the biology and pathogenesis of its causative agent SARS-CoV-2. Despite intense scrutiny, several proteins encoded by the genomes of SARS-CoV-2 and other SARS-like coronaviruses remain enigmatic. Moreover, the high infectivity and severity of SARS-CoV-2 in certain individuals make wet-lab studies currently challenging. In this study, we used a series of computational strategies to identify several fast-evolving regions of SARS-CoV-2 proteins which are potentially under host immune pressure. Most notably, the hitherto-uncharacterized protein encoded by ORF8 is one of them. Using sensitive sequence and structural analysis methods, we show that ORF8 and several other proteins from alpha- and beta-coronavirus comprise novel families of immunoglobulin domain proteins, which might function as potential immune modulators to delay or attenuate the host immune response against the viruses.


Subject(s)
Coronavirus/genetics , Coronavirus/pathogenicity , Evolution, Molecular , Viral Proteins/genetics , Virulence Factors/genetics , Amino Acid Sequence , Animals , Betacoronavirus/chemistry , Betacoronavirus/classification , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Coronavirus/chemistry , Coronavirus/classification , Genome, Viral/genetics , Host Specificity , Humans , Immunoglobulin Domains/genetics , Models, Molecular , Open Reading Frames , Phylogeny , Viral Proteins/chemistry , Virulence Factors/chemistry
15.
Front Biosci (Landmark Ed) ; 25: 1894-1900, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-422434

ABSTRACT

We analyzed the nucleocapsid and surface proteins from several Coronaviridae viruses using an alignment-free computer program. Three isolates of novel, human coronavirus (SARS0CoV-2) (2019) that are responsible for the current pandemic and older SARS strains of human and animal coronaviruses were examined. The nucleocapsid and glycoprotein sequences are identical for the three novel 2019 human isolates and they are closely related to these sequences in six bat and human SARS coronaviruses. This strongly supports the bat origin of the pandemic, novel coronavirus. One surface glycoprotein fragment of 111 amino acids is the largest, conserved, common permutation in the examined bat SARS-like and human SARS viruses, including the Covid-19 virus. BLAST analysis confirmed that this fragment is conserved only in the human and bat SARS strains. This fragment likely is involved in infectivity and is of interest for vaccine development. Surface glycoprotein and nucleocapsid protein sequence homologies of 58.9% and 82.5%, respectively, between the novel SARS0CoV-2 strains and the human SARS (2018) virus suggest that existing anti-SARS vaccines may provide some protection against the novel coronavirus.


Subject(s)
Betacoronavirus/genetics , Coronaviridae/genetics , Coronavirus Infections , Nucleocapsid Proteins/genetics , Pandemics , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/genetics , Algorithms , Amino Acid Sequence , Animals , Chiroptera/virology , Coronaviridae/classification , Genome, Viral/genetics , Humans , Software , Species Specificity , Viral Envelope Proteins/genetics
16.
Drugs ; 80(10): 941-946, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-361231

ABSTRACT

G-Quadruplexes (G4s) are non-canonical secondary structures formed within guanine-rich regions of DNA or RNA. G4 sequences/structures have been detected in human and in viral genomes, including Coronaviruses Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2. Here, we outline the existing evidence indicating that G4 ligands and inhibitors of SARS-CoV-2 helicase may exert some antiviral activity reducing viral replication and can represent a potential therapeutic approach to tackle the COVID-19 pandemic due to SARS-CoV-2 infection. We also discuss how repositioning of FDA-approved drugs against helicase activity of other viruses, could represent a rapid strategy to limit deaths associated with COVID-19 pandemic.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/genetics , Coronavirus Infections/drug therapy , G-Quadruplexes , Genome, Viral/genetics , Pneumonia, Viral/drug therapy , RNA Helicases/antagonists & inhibitors , Drug Repositioning , Humans , Methyltransferases/antagonists & inhibitors , Pandemics , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
17.
Cells ; 9(5)2020 05 20.
Article in English | MEDLINE | ID: covidwho-324261

ABSTRACT

The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development of targeted therapeutic interventions. The replication of the viral genome within the infected cells is a key stage of the SARS-CoV-2 life cycle. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. This review provides an update of the structural and functional data on the key actors of the replicatory machinery of SARS-CoV-2, to fill the gaps in the currently available structural data, which is mainly obtained through homology modeling. Moreover, learning from similar viruses, we collect data from the literature to reconstruct the pattern of interactions among the protein actors of the SARS-CoV-2 RNA polymerase machinery. Here, an important role is played by co-factors such as Nsp8 and Nsp10, not only as allosteric activators but also as molecular connectors that hold the entire machinery together to enhance the efficiency of RNA replication.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Pneumonia, Viral/virology , RNA, Viral/metabolism , Virus Replication/physiology , Animals , Catalytic Domain , DNA-Directed RNA Polymerases/metabolism , Exoribonucleases/chemistry , Exoribonucleases/metabolism , Genome, Viral/genetics , Humans , Methyltransferases/chemistry , Methyltransferases/metabolism , Pandemics , Protein Conformation, alpha-Helical , RNA Helicases/chemistry , RNA Helicases/metabolism , RNA, Messenger/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/chemistry , Viral Regulatory and Accessory Proteins/metabolism
18.
Nature ; 583(7816): 437-440, 2020 07.
Article in English | MEDLINE | ID: covidwho-326050

ABSTRACT

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Host-Pathogen Interactions/immunology , Lymphopenia/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Distress Syndrome, Adult/virology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Animals , Asymptomatic Infections/epidemiology , Betacoronavirus/classification , Betacoronavirus/isolation & purification , China/epidemiology , Cohort Studies , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Critical Illness/epidemiology , Disease Progression , Evolution, Molecular , Female , Genetic Variation , Genome, Viral/genetics , Hospitalization/statistics & numerical data , Humans , Inflammation Mediators/immunology , Interleukin-6/blood , Interleukin-6/immunology , Interleukin-8/blood , Interleukin-8/immunology , Lymphocyte Count , Lymphopenia/complications , Male , Middle Aged , Pandemics , Phylogeny , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Respiratory Distress Syndrome, Adult/complications , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Time Factors , Treatment Outcome , Virulence/genetics , Virus Shedding , Young Adult , Zoonoses/transmission , Zoonoses/virology
19.
Nature ; 583(7815): 286-289, 2020 07.
Article in English | MEDLINE | ID: covidwho-210764

ABSTRACT

The current outbreak of coronavirus disease-2019 (COVID-19) poses unprecedented challenges to global health1. The new coronavirus responsible for this outbreak-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-shares high sequence identity to SARS-CoV and a bat coronavirus, RaTG132. Although bats may be the reservoir host for a variety of coronaviruses3,4, it remains unknown whether SARS-CoV-2 has additional host species. Here we show that a coronavirus, which we name pangolin-CoV, isolated from a Malayan pangolin has 100%, 98.6%, 97.8% and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S proteins, respectively. In particular, the receptor-binding domain of the S protein of pangolin-CoV is almost identical to that of SARS-CoV-2, with one difference in a noncritical amino acid. Our comparative genomic analysis suggests that SARS-CoV-2 may have originated in the recombination of a virus similar to pangolin-CoV with one similar to RaTG13. Pangolin-CoV was detected in 17 out of the 25 Malayan pangolins that we analysed. Infected pangolins showed clinical signs and histological changes, and circulating antibodies against pangolin-CoV reacted with the S protein of SARS-CoV-2. The isolation of a coronavirus from pangolins that is closely related to SARS-CoV-2 suggests that these animals have the potential to act as an intermediate host of SARS-CoV-2. This newly identified coronavirus from pangolins-the most-trafficked mammal in the illegal wildlife trade-could represent a future threat to public health if wildlife trade is not effectively controlled.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Eutheria/virology , Evolution, Molecular , Genome, Viral/genetics , Sequence Homology, Nucleic Acid , Animals , Betacoronavirus/classification , China , Chiroptera/virology , Chlorocebus aethiops , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/transmission , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Disease Reservoirs/virology , Genomics , Host Specificity , Humans , Lung/pathology , Lung/virology , Malaysia , Nucleocapsid Proteins/genetics , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Polymerase Chain Reaction , Recombination, Genetic , Sequence Alignment , Sequence Analysis, RNA , Spike Glycoprotein, Coronavirus/genetics , Vero Cells , Viral Envelope Proteins/genetics , Viral Matrix Proteins/genetics , Zoonoses/transmission , Zoonoses/virology
20.
Iran J Kidney Dis ; 14(3): 167-172, 2020 05.
Article in English | MEDLINE | ID: covidwho-170321

ABSTRACT

Coronaviruses primarily cause zoonotic infections, however in the past few decades several interspecies transmissions have occurred, the last one by SARS-CoV-2, causing COVID-19 pandemic, posing serious threat to global health. The SARS-CoV-2 spike (S) protein plays an important role in viral attachment, fusion and entry. However, other structural and non-structural SARS-CoV-2 proteins are potential influencers in virus pathogenicity. Among these proteins; Orf3, Orf8, and Orf10 show the least homology to SARSCoV proteins and therefore should be further studied for their abilities to modulate antiviral and inflammatory responses. Here, we discuss how SARS-COV-2 interacts with our immune system.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/virology , Genome, Viral/genetics , Immune System/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Viral Proteins/genetics , Viral Proteins/metabolism , Animals , Betacoronavirus/genetics , Betacoronavirus/immunology , Gene Order , Humans , Pandemics , SARS Virus/genetics , SARS Virus/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Structures/genetics , Virus Internalization
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