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1.
Cell ; 2022.
Article in English | ScienceDirect | ID: covidwho-2031185

ABSTRACT

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4 and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337677

ABSTRACT

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2. Highlights Spike L452R/Q/M mutations increase the effective reproduction number of BA.2 BA.4/5 is resistant to the immunity induced by BA.1 and BA.2 infections BA.2.12.1 and BA.4/5 more efficiently spread in human lung cells than BA.2 BA.4/5 is more pathogenic than BA.2 in hamsters

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335276

ABSTRACT

As of May 2022, Omicron BA.2 variant is the most dominant variant in the world. Thereafter, Omicron subvariants have emerged and some of them began outcompeting BA.2 in multiple countries. For instance, Omicron BA.2.11, BA.2.12.1 and BA.4/5 subvariants are becoming dominant in France, the USA and South Africa, respectively. In this study, we evaluated the sensitivity of these new Omicron subvariants (BA.2.11, BA.2.12.1 and BA.4/5) to eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab). Notably, we showed that although cilgavimab is antiviral against BA.2, BA.4/5 exhibits higher resistance to this antibody compared to BA.2. Since mutations are accumulated in the spike proteins of newly emerging SARS-CoV-2 variants, we suggest the importance of rapid evaluation of the efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants.

5.
Cell ; 185(12): 2103-2115.e19, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-1814233

ABSTRACT

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.


Subject(s)
COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , COVID-19/virology , Cricetinae , Epithelial Cells , Humans , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics
6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332336

ABSTRACT

Recent studies have revealed the unique virological characteristics of Omicron, the newest SARS-CoV-2 variant of concern, such as pronounced resistance to vaccine-induced neutralizing antibodies, less efficient cleavage of the spike protein, and poor fusogenicity. However, it remains unclear which mutation(s) in the spike protein determine the virological characteristics of Omicron. Here, we show that the representative characteristics of the Omicron spike are determined by its receptor-binding domain. Interestingly, the molecular phylogenetic analysis revealed that the acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidate that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue in another protomer in the spike trimer, which confers the attenuated spike cleavage efficiency and fusogenicity of Omicron. Our data shed light on the evolutionary events underlying Omicron emergence at the molecular level. Highlights Omicron spike receptor binding domain determines virological characteristics Spike S375F mutation results in the poor spike cleavage and fusogenicity in Omicron Acquisition of the spike S375F mutation triggered the explosive spread of Omicron F375-H505-mediated π-π interaction in the spike determines the phenotype of Omicron

7.
Nature ; 603(7902): 706-714, 2022 03.
Article in English | MEDLINE | ID: covidwho-1764186

ABSTRACT

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.


Subject(s)
COVID-19/pathology , COVID-19/virology , Membrane Fusion , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cell Line , Cell Membrane/metabolism , Cell Membrane/virology , Chlorocebus aethiops , Convalescence , Female , Humans , Immune Sera/immunology , Intestines/pathology , Intestines/virology , Lung/pathology , Lung/virology , Male , Middle Aged , Mutation , Nasal Mucosa/pathology , Nasal Mucosa/virology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Tissue Culture Techniques , Virulence , Virus Replication
8.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327671

ABSTRACT

Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineage, BA.1 (ref 1, 2 ), another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314228

ABSTRACT

The presence of an ORF6 gene distinguishes Sarbecoviruses such as SARS-CoV and SARS-CoV-2 from other Betacoronaviruses. Here, we show that ORF6 inhibits the induction of type I IFN upon viral infection, as well as IFN types I and III signaling. Intriguingly, the anti-IFN activity of ORF6 proteins of SARS-CoV-2 lineages is more potent than that of SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as determinants of the potent IFN-antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that ORF6 binds to RAE1 and NUP98 via its C-terminus, thereby inhibiting the nuclear export of IFNB1 mRNA. Finally, we identify natural occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Altogether, our findings suggest that ORF6 contributes to the poor IFN activation observed in COVID-19 patients. Furthermore, the emergence of SARS-CoV-2 variants without functional ORF6 may contribute to the attenuation of viral pathogenicity.Funding: This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.) and 20fk0108270 (to K.S.);AMED Research Program on HIV/AIDS 19fk0410019 (to K.S.) and 20fk0410014 (to K.S.);JST J-RAPID JPMJJR2007 (to K.S.);KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.), KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.) and 19H04826 (to K.S.), and Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.);JSPS Research Fellow DC1 19J20488 (to I.K.) and DC1 19J22914 (to Y.K.);ONO Medical Research Foundation (to K.S.);Ichiro Kanehara Foundation (to K.S.);Lotte Foundation (to K.S.);Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.);Daiichi Sankyo Foundation of Life Science (to K.S.);Sumitomo Foundation (to K.S.);Uehara Foundation (to K.S.);Takeda Science Foundation (to K.S.);JSPS Core-to-Core program (A. Advanced Research Networks) (to K.S.);the Canon Foundation in Europe (to. D.S. and K.S.);a COVID19 Research Grant of the Federal Ministry of Education and Research (MWK) Baden-Württemberg (to. D.S.);2020 Tokai University School of Medicine Research Aid (to S.N.);and International Joint Research Project of the Institute of Medical Science, the University of Tokyo 2020-K3003 (to D.S. and K.S.). Conflict of Interest: The authors declare that no competing interests exist.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-317457

ABSTRACT

Many variants that naturally acquire multiple mutations have emerged during the current SARS-CoV-2 pandemic, which is devastating societies worldwide. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here, we demonstrate that two recently emerging mutations in the receptor - binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce the affinity toward the viral receptor ACE2;notably, the L452R mutation increases spike stability and viral infectivity and potentially promotes viral replication. Our data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.Funding: This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108163 (to A.S.), 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.), 20fk0108270 (to K.S.) and 20fk0108413 (to T.I., S.N. and K.S.);AMED Research Program on HIV/AIDS 20fk0410019 (to T.U. and K.S.), 20fk0410014 (to K.S.) and 21fk0410039 (to K.S.);AMED Japan Program for Infectious Diseases Research and Infrastructure 20wm0325009 (to A.S.);JST J RAPID JPMJJR2007 (to K.S.);JST SICORP (e-ASIA) JPMJSC20U1 (to K.S.);JSTCREST JPMJCR20H6 (to S.N) and JPMJCR20H4 (to K.S);JSPS KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.) and 21H02737 (to K.S.);JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.) and 19H04826 (to K.S.);JSPS Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.);JSPS Core-to-Core Program JPJSCCB20190009 (to T.U.) andJPJSCCA20190008 (A. Advanced Research Networks) (to K.S.);JSPS Research Fellow DC1 19J20488 (to I.K.);JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to T.I.);ONO Medical Research Foundation (to K.S.);Ichiro Kanehara Foundation (to K.S.);Lotte Foundation (to K.S.);Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.);Daiichi Sankyo Foundation of Life Science (to K.S.);Sumitomo Foundation (to K.S.);Uehara Foundation (to K.S.);Takeda Science Foundation (to C.M., T.I. and K.S.);The Tokyo Biochemical Research Foundation (to K.S.);Mitsubishi Foundation (to T.I.);Shin Nihon Foundation of Advanced Medical Research (to T.I.);An intramural grant from Kumamoto University COVID-19 Research Projects (AMABIE) (to C.M., T.I. and T.U.);Kumamoto University International Collaborative Research Grants (to T.U.);Intercontinental Research and Educational Platform Aiming for Eradication of HIV/AIDS (to T.I. and T.U.);2020 Tokai University School of Medicine Research Aid (to S.N.);and Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (to K.S.). T.S.T and I.N. are the recipients of the doctoral course scholarship from Japanese Government.Conflict of Interest: The authors declare that no competing interests exist.Ethical Approval: All protocols involving human subjects recruited at Kyushu University Hospital, Japan, National Hospital Organization Kyushu Medical Center, Japan, and Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan, were reviewed and approved by the Ethics Committee for Epidemiological andGeneral Research at the Faculty of Life Science, Kumamoto University (approval numbers 2066 and 461). All human subjects provided written informed consent.

11.
Nature ; 603(7902): 700-705, 2022 03.
Article in English | MEDLINE | ID: covidwho-1661969

ABSTRACT

The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.


Subject(s)
COVID-19/pathology , COVID-19/virology , Membrane Fusion , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization , Animals , COVID-19/epidemiology , Cell Line , Cricetinae , Humans , In Vitro Techniques , Lung/pathology , Lung/virology , Male , Mesocricetus , Mutation , SARS-CoV-2/classification , SARS-CoV-2/growth & development , South Africa/epidemiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virulence , Virus Replication
12.
Cell Rep ; 38(2): 110218, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1588140

ABSTRACT

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.


Subject(s)
COVID-19/immunology , Immunity/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , Female , Glycosylation , HEK293 Cells , Humans , Male , Middle Aged , Mutation/immunology , Spike Glycoprotein, Coronavirus/immunology
13.
Nature ; 602(7896): 300-306, 2022 02.
Article in English | MEDLINE | ID: covidwho-1532072

ABSTRACT

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society1. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2). However, the virological properties of B.1.617.2/Delta remain unclear. Here we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.


Subject(s)
COVID-19/virology , Membrane Fusion , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/epidemiology , Cricetinae , Giant Cells/metabolism , Giant Cells/virology , Male , Mesocricetus , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Virulence/genetics , Virus Replication
15.
J Infect Dis ; 224(6): 989-994, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1429251

ABSTRACT

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine-elicited neutralizing antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immune Evasion , Mutation , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , Chlorocebus aethiops , HEK293 Cells , Humans , India , Protein Binding , SARS-CoV-2/immunology , Serine Endopeptidases , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
16.
Cell Host Microbe ; 29(7): 1124-1136.e11, 2021 07 14.
Article in English | MEDLINE | ID: covidwho-1272337

ABSTRACT

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.


Subject(s)
COVID-19/virology , Immunity, Cellular , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2 , COVID-19/epidemiology , Genome, Viral , Humans , Mutation , Phylogeny , Protein Binding , Viral Proteins/genetics , Virus Replication
17.
Cell Rep ; 34(13): 108916, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1128920

ABSTRACT

The presence of an ORF6 gene distinguishes sarbecoviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 from other betacoronaviruses. Here we show that ORF6 inhibits induction of innate immune signaling, including upregulation of type I interferon (IFN) upon viral infection as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and that ORF6 inhibits nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Our findings suggest that ORF6 contributes to the poor IFN activation observed in individuals with coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19/metabolism , Interferon Type I/metabolism , Viral Proteins/metabolism , Animals , COVID-19/genetics , Chlorocebus aethiops , HEK293 Cells , Humans , Immunity, Innate/immunology , SARS-CoV-2/isolation & purification , Signal Transduction/immunology , Vero Cells , Viral Proteins/genetics
18.
PLoS Pathog ; 16(9): e1008812, 2020 09.
Article in English | MEDLINE | ID: covidwho-829129

ABSTRACT

The APOBEC3 deaminases are potent inhibitors of virus replication and barriers to cross-species transmission. For simian immunodeficiency virus (SIV) to transmit to a new primate host, as happened multiple times to seed the ongoing HIV-1 epidemic, the viral infectivity factor (Vif) must be capable of neutralizing the APOBEC3 enzymes of the new host. Although much is known about current interactions of HIV-1 Vif and human APOBEC3s, the evolutionary changes in SIV Vif required for transmission from chimpanzees to gorillas and ultimately to humans are poorly understood. Here, we demonstrate that gorilla APOBEC3G is a factor with the potential to hamper SIV transmission from chimpanzees to gorillas. Gain-of-function experiments using SIVcpzPtt Vif revealed that this barrier could be overcome by a single Vif acidic amino acid substitution (M16E). Moreover, degradation of gorilla APOBEC3F is induced by Vif through a mechanism that is distinct from that of human APOBEC3F. Thus, our findings identify virus adaptations in gorillas that preceded and may have facilitated transmission to humans.


Subject(s)
APOBEC-3G Deaminase/metabolism , Evolution, Molecular , Gene Products, vif/metabolism , Host-Pathogen Interactions , Simian Acquired Immunodeficiency Syndrome/transmission , Simian Immunodeficiency Virus/isolation & purification , Virus Replication , APOBEC-3G Deaminase/chemistry , APOBEC-3G Deaminase/genetics , Amino Acid Sequence , Animals , Gene Products, vif/chemistry , Gene Products, vif/genetics , Gorilla gorilla , Humans , Pan troglodytes , Phylogeny , Protein Conformation , Sequence Homology , Simian Acquired Immunodeficiency Syndrome/virology
19.
Cell Rep ; 32(12): 108185, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-743905

ABSTRACT

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Interferon Type I/antagonists & inhibitors , Pneumonia, Viral/virology , Viral Regulatory and Accessory Proteins/genetics , Adult , Amino Acid Sequence/genetics , Animals , Betacoronavirus/immunology , COVID-19 , Chiroptera/virology , Codon, Nonsense/genetics , Coronavirus Infections/pathology , Eutheria/virology , Humans , Male , Pandemics , SARS-CoV-2 , Viral Regulatory and Accessory Proteins/metabolism
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