Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiologic agent of the current coronavirus disease 2019(COVID-19)pandemic,has evolved to adapt to human host and transmission over the past 12 months.One...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiologic agent of the current coronavirus disease 2019(COVID-19)pandemic,has evolved to adapt to human host and transmission over the past 12 months.One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein(D614G),which has become dominant in the currently circulating virus strains.Since spike protein determines host ranges,tissue tropism,and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2(ACE2),the D614G mutation is hypothesized to enhance viral fitness in human host,leading to increased transmission during the global pandemic.Here we summarize the recent progress on the role of the D614G mutation in viral replication,pathogenesis,transmission,and vaccine and therapeutic antibody development.These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.展开更多
After 56 days without coronavirus disease 2019(COVID-19)cases,reemergent cases were reported in Beijing,China on June 11,2020.Here,we report the genetic characteristics of severe acute respiratory syndrome coronavirus...After 56 days without coronavirus disease 2019(COVID-19)cases,reemergent cases were reported in Beijing,China on June 11,2020.Here,we report the genetic characteristics of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)sequenced from the clinical specimens of 4 human cases and 2 environmental samples.The nucleotide similarity among six SARS-CoV-2 genomes ranged from 99.98%to 99.99%.Compared with the reference strain of SARS-CoV-2(GenBank No.NC_045512),all six genome sequences shared the same substitutions at nt241(C→T),nt3037(C→T),nt14408(C→T),nt23403(A→G),nt28881(G→A),nt28882(G→A),and nt28883(G→C),which are the characteristic nucleotide substitutions of L-lineage European branch I.This was also proved by themaximum likelihood phylogenetic tree based on the full-length genome of SARS-CoV-2.They also have a unique shared nucleotide substitution,nt6026(C→T),which is the characteristic nucleotide substitution of SARS-CoV-2 in Beijing's Xinfadi outbreak.It is noteworthy that there is an amino acid D614Gmutation caused by nt23403 substitution in all six genomes,which may enhance the virus's infectivity in humans and help it become the leading strain of the virus to spread around the world today.It is necessary to continuously monitor the genetic variation of SARS-CoV-2,focusing on the influence of key mutation sites of SARS-CoV-2 on viral transmission,clinical manifestations,severity,and course of disease.展开更多
The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop r...The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop resistance are in urgent need.Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture,there are few confirmed antiviral candidates in vivo.In this study,94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs.Among them,24 compounds with low cytotoxicity were selected,and of these,17 compounds also effectively suppressed SARS-CoV-2 infection in He La cells transduced with human ACE2.Six compounds disturb multiple processes of the SARSCoV-2 life cycle.Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2infection.Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant.Except for cisatracurium,six compounds reduced hamster pulmonary viral load,and IL-6 and TNF-αm RNAwhen assayed at 4 d postinfection.In particular,sertraline,salinomycin,and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro,suggesting promising application for COVID-19 treatment.展开更多
With the COVID-19 pandemic, disparities between the infection rate and death rate in different countries become a major concern. In some countries, lower mortality rate compared to others can be explained by better te...With the COVID-19 pandemic, disparities between the infection rate and death rate in different countries become a major concern. In some countries, lower mortality rate compared to others can be explained by better testing capacity and intensive care facilities. Complete SARS-CoV-2 genome sequences from different countries of the world are continually submitted to Global Initiative for Sharing All Influenza Data using Next Generation Sequencing method. A SARS-CoV-2 variant with a D 614G Mutation in the spike (S) protein has become the most dominant form in the global pandemic. There are a number of ongoing studies trying to relate this mutation with the infectivity, mortality, transmissibility of the virus and its impact on vaccine development. This review aims to accumulate the major findings from some of these studies and focus its future implication. Some studies suggested D 614G strain has increased binding capacity, it affects more cells at a faster rate, so has a high transmissibility. Patients infected with this strain were found with high viral load. But still now there is no such evidence that this strain produces more severe disease as well as increased mortality. The structural change of spike protein produced by D 614G mutation was minor and did not hamper the vaccine efficacy. Some studies showed antibodies produced against D614 strain can neutralize G614 strain and <em>vice versa</em>. Whenever a mutation occurs in spike protein there are always chances of affecting the infectivity, transmissibility, vaccine efficacy. Therefore, more studies are required to find out the overall effect of D 614G mutation.展开更多
We examined the coronavirus classification and evolution through its multiple mutations that have increased its transmissibility rate up to 70% globally, threatening to undermine the promise of a number of emerging va...We examined the coronavirus classification and evolution through its multiple mutations that have increased its transmissibility rate up to 70% globally, threatening to undermine the promise of a number of emerging vaccines that primarily focus on the immune detection of the Spike trimer. The safety and effectiveness of different vaccination methods are evaluated and compared, including the mRNA version, the Adenovirus DNA, Spike protein subunits, the deactivated virus genres, and the live attenuated coronavirus. Mutations have been long considered as random events, or mistakes during the viral RNA replication. Usually, what can go wrong will go wrong;therefore, repeated transformations lead to the extinction of a virus. On the contrary, the aggregate result of over 300,000 Covid-19 variants has expanded its transmissibility and infectiousness. Covid-19 mutations do not degrade the virus;they empower and facilitate its disguise to evade detection. Unlike other coronaviruses, Covid-19 amino acid switches do not reflect the random unfolding of errors that eventually eradicate the virus. Covid-19 appears to use mutations adaptively in the service of its survival and expansion. We cite evidence that Covid-19 inhibits the interferon type I production, compromising adaptive immunity from recognizing the virus. The deleterious consequences of the cytokine storm where the CD8+ killer cells injure the vital organs of the host may well be a Covid-19 manoeuvring to escape exposure. It is probable that evolution has programmed Covid-19 with an adeptness designed to debilitate key systemic defences to secure its subsistence. To date the infectiousness of the Covid-19 pandemic is exponentially increasing, denoting the possibility of an even more dangerously elusive, inconspicuous, and sophisticated version of the disease.展开更多
The coronavirus diseases 2019(COVID-19)caused by the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 has caused more than 140 million infections worldwide by the end of...The coronavirus diseases 2019(COVID-19)caused by the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 has caused more than 140 million infections worldwide by the end of April 2021.As an enveloped single-stranded positive-sense RNA virus,SARS-CoV-2 underwent constant evolution that produced novel variants carrying mutation conferring fitness advantages.The current prevalent D614G variant,with glycine substituted for aspartic acid at position 614 in the spike glycoprotein,is one of such variants that became the main circulating strain worldwide in a short period of time.Over the past year,intensive studies from all over the world had defined the epidemiological characteristics of this highly contagious variant and revealed the underlying mechanisms.This review aims at presenting an overall picture of the impacts of D614G mutation on virus transmission,elucidating the underlying mechanisms of D614G in virus pathogenicity,and providing insights into the development of effective therapeutics.展开更多
We traced the coronavirus classification and evolution,analyzed the Covid-19 composition and its distinguishing characteristics when compared to SARS-CoV and MERS-CoV.Despite their close kinship,SARS-CoV and Covid-19 ...We traced the coronavirus classification and evolution,analyzed the Covid-19 composition and its distinguishing characteristics when compared to SARS-CoV and MERS-CoV.Despite their close kinship,SARS-CoV and Covid-19 display significant structural differences,including 380 amino acid substitutions,and variable homology between certain open reading frames that are bound to diversify the pathogenesis and virulence of the two viral compounds.A single amino acid substitution such as replacing Aspartate(D)with Glycine(G)composes the D614G mutation that is around 20%more infectious than its predecessor 614D.The B117 variant,that exhibits a 70%transmissibility rate,harbours 23 mutants,each reflecting one amino acid exchange.We examined several globally spreading mutations,501.V2,B1351,P1,and others,with respect to the specific amino acid conversions involved.Unlike previous versions of coronavirus,where random mutations eventually precipitate extinction,the multiplicity of over 300,000 mutations appears to have rendered Covid-19 more contagious,facilitating its ability to evade detection,thus challenging the effectiveness of a large variety of emerging vaccines.Vaccination enhances immune memory and intelligence to combat or obstruct viral entry by generating antibodies that will prohibit the cellular binding and fusion with the Spike protein,restricting the virus from releasing its contents into the cell.Developing antibodies during the innate response,appears to be the most compelling solution in light of the hypothesis that Covid-19 inhibits the production of Interferon type I,compromising adaptive efficiency to recognize the virus,possibly provoking a cytokine storm that injures vital organs.With respect to that perspective,the potential safety and effectiveness of different vaccines are evaluated and compared,including the Spike protein mRNA version,the Adenovirus DNA,Spike protein subunits,the deactivated virus genres,or,finally,the live attenuated coronavirus that appears to demonstrate the greatest effectiveness展开更多
The SARS-CoV-2 Omicron variants are notorious for their transmissibility,but little is known about their subgenomic RNA(sgRNA)expression.This study applied RNA-seq to delineate the quantitative and qualitative profile...The SARS-CoV-2 Omicron variants are notorious for their transmissibility,but little is known about their subgenomic RNA(sgRNA)expression.This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern(non-VOC)-D614G.A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOCD614G regardless of host gender,age and presence of pneumonia.Remarkably,such profile was lost in samples with low viral load,suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point.A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G.The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load(AUC¼0.91,95%CI 0.88–0.94),and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient.Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.展开更多
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiologic agent of the current coronavirus disease 2019(COVID-19)pandemic,has evolved to adapt to human host and transmission over the past 12 months.One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein(D614G),which has become dominant in the currently circulating virus strains.Since spike protein determines host ranges,tissue tropism,and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2(ACE2),the D614G mutation is hypothesized to enhance viral fitness in human host,leading to increased transmission during the global pandemic.Here we summarize the recent progress on the role of the D614G mutation in viral replication,pathogenesis,transmission,and vaccine and therapeutic antibody development.These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.
基金supported by the National Science and Technology Major Project of China(Project No.2017ZX10104001,2018ZX10711001).
文摘After 56 days without coronavirus disease 2019(COVID-19)cases,reemergent cases were reported in Beijing,China on June 11,2020.Here,we report the genetic characteristics of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)sequenced from the clinical specimens of 4 human cases and 2 environmental samples.The nucleotide similarity among six SARS-CoV-2 genomes ranged from 99.98%to 99.99%.Compared with the reference strain of SARS-CoV-2(GenBank No.NC_045512),all six genome sequences shared the same substitutions at nt241(C→T),nt3037(C→T),nt14408(C→T),nt23403(A→G),nt28881(G→A),nt28882(G→A),and nt28883(G→C),which are the characteristic nucleotide substitutions of L-lineage European branch I.This was also proved by themaximum likelihood phylogenetic tree based on the full-length genome of SARS-CoV-2.They also have a unique shared nucleotide substitution,nt6026(C→T),which is the characteristic nucleotide substitution of SARS-CoV-2 in Beijing's Xinfadi outbreak.It is noteworthy that there is an amino acid D614Gmutation caused by nt23403 substitution in all six genomes,which may enhance the virus's infectivity in humans and help it become the leading strain of the virus to spread around the world today.It is necessary to continuously monitor the genetic variation of SARS-CoV-2,focusing on the influence of key mutation sites of SARS-CoV-2 on viral transmission,clinical manifestations,severity,and course of disease.
基金supported by the National Natural Science Foundation of China(31570170)the National Key Research and Development Program of China(2016YFC1200401)。
文摘The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop resistance are in urgent need.Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture,there are few confirmed antiviral candidates in vivo.In this study,94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs.Among them,24 compounds with low cytotoxicity were selected,and of these,17 compounds also effectively suppressed SARS-CoV-2 infection in He La cells transduced with human ACE2.Six compounds disturb multiple processes of the SARSCoV-2 life cycle.Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2infection.Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant.Except for cisatracurium,six compounds reduced hamster pulmonary viral load,and IL-6 and TNF-αm RNAwhen assayed at 4 d postinfection.In particular,sertraline,salinomycin,and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro,suggesting promising application for COVID-19 treatment.
文摘With the COVID-19 pandemic, disparities between the infection rate and death rate in different countries become a major concern. In some countries, lower mortality rate compared to others can be explained by better testing capacity and intensive care facilities. Complete SARS-CoV-2 genome sequences from different countries of the world are continually submitted to Global Initiative for Sharing All Influenza Data using Next Generation Sequencing method. A SARS-CoV-2 variant with a D 614G Mutation in the spike (S) protein has become the most dominant form in the global pandemic. There are a number of ongoing studies trying to relate this mutation with the infectivity, mortality, transmissibility of the virus and its impact on vaccine development. This review aims to accumulate the major findings from some of these studies and focus its future implication. Some studies suggested D 614G strain has increased binding capacity, it affects more cells at a faster rate, so has a high transmissibility. Patients infected with this strain were found with high viral load. But still now there is no such evidence that this strain produces more severe disease as well as increased mortality. The structural change of spike protein produced by D 614G mutation was minor and did not hamper the vaccine efficacy. Some studies showed antibodies produced against D614 strain can neutralize G614 strain and <em>vice versa</em>. Whenever a mutation occurs in spike protein there are always chances of affecting the infectivity, transmissibility, vaccine efficacy. Therefore, more studies are required to find out the overall effect of D 614G mutation.
文摘We examined the coronavirus classification and evolution through its multiple mutations that have increased its transmissibility rate up to 70% globally, threatening to undermine the promise of a number of emerging vaccines that primarily focus on the immune detection of the Spike trimer. The safety and effectiveness of different vaccination methods are evaluated and compared, including the mRNA version, the Adenovirus DNA, Spike protein subunits, the deactivated virus genres, and the live attenuated coronavirus. Mutations have been long considered as random events, or mistakes during the viral RNA replication. Usually, what can go wrong will go wrong;therefore, repeated transformations lead to the extinction of a virus. On the contrary, the aggregate result of over 300,000 Covid-19 variants has expanded its transmissibility and infectiousness. Covid-19 mutations do not degrade the virus;they empower and facilitate its disguise to evade detection. Unlike other coronaviruses, Covid-19 amino acid switches do not reflect the random unfolding of errors that eventually eradicate the virus. Covid-19 appears to use mutations adaptively in the service of its survival and expansion. We cite evidence that Covid-19 inhibits the interferon type I production, compromising adaptive immunity from recognizing the virus. The deleterious consequences of the cytokine storm where the CD8+ killer cells injure the vital organs of the host may well be a Covid-19 manoeuvring to escape exposure. It is probable that evolution has programmed Covid-19 with an adeptness designed to debilitate key systemic defences to secure its subsistence. To date the infectiousness of the Covid-19 pandemic is exponentially increasing, denoting the possibility of an even more dangerously elusive, inconspicuous, and sophisticated version of the disease.
基金supported by the National Key Research&Development Program of China(2018YFA0900804)the National Natural Science Foundation of China(31970685).
文摘The coronavirus diseases 2019(COVID-19)caused by the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 has caused more than 140 million infections worldwide by the end of April 2021.As an enveloped single-stranded positive-sense RNA virus,SARS-CoV-2 underwent constant evolution that produced novel variants carrying mutation conferring fitness advantages.The current prevalent D614G variant,with glycine substituted for aspartic acid at position 614 in the spike glycoprotein,is one of such variants that became the main circulating strain worldwide in a short period of time.Over the past year,intensive studies from all over the world had defined the epidemiological characteristics of this highly contagious variant and revealed the underlying mechanisms.This review aims at presenting an overall picture of the impacts of D614G mutation on virus transmission,elucidating the underlying mechanisms of D614G in virus pathogenicity,and providing insights into the development of effective therapeutics.
文摘We traced the coronavirus classification and evolution,analyzed the Covid-19 composition and its distinguishing characteristics when compared to SARS-CoV and MERS-CoV.Despite their close kinship,SARS-CoV and Covid-19 display significant structural differences,including 380 amino acid substitutions,and variable homology between certain open reading frames that are bound to diversify the pathogenesis and virulence of the two viral compounds.A single amino acid substitution such as replacing Aspartate(D)with Glycine(G)composes the D614G mutation that is around 20%more infectious than its predecessor 614D.The B117 variant,that exhibits a 70%transmissibility rate,harbours 23 mutants,each reflecting one amino acid exchange.We examined several globally spreading mutations,501.V2,B1351,P1,and others,with respect to the specific amino acid conversions involved.Unlike previous versions of coronavirus,where random mutations eventually precipitate extinction,the multiplicity of over 300,000 mutations appears to have rendered Covid-19 more contagious,facilitating its ability to evade detection,thus challenging the effectiveness of a large variety of emerging vaccines.Vaccination enhances immune memory and intelligence to combat or obstruct viral entry by generating antibodies that will prohibit the cellular binding and fusion with the Spike protein,restricting the virus from releasing its contents into the cell.Developing antibodies during the innate response,appears to be the most compelling solution in light of the hypothesis that Covid-19 inhibits the production of Interferon type I,compromising adaptive efficiency to recognize the virus,possibly provoking a cytokine storm that injures vital organs.With respect to that perspective,the potential safety and effectiveness of different vaccines are evaluated and compared,including the Spike protein mRNA version,the Adenovirus DNA,Spike protein subunits,the deactivated virus genres,or,finally,the live attenuated coronavirus that appears to demonstrate the greatest effectiveness
基金supported by the Food and Health Bureau,Hong Kong SAR Government(reference no.COVID19F06).
文摘The SARS-CoV-2 Omicron variants are notorious for their transmissibility,but little is known about their subgenomic RNA(sgRNA)expression.This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern(non-VOC)-D614G.A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOCD614G regardless of host gender,age and presence of pneumonia.Remarkably,such profile was lost in samples with low viral load,suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point.A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G.The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load(AUC¼0.91,95%CI 0.88–0.94),and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient.Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.
