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1.
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
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334187

ABSTRACT

Although the Omicron variant of the SARS-CoV-2 virus is resistant to neutralizing antibodies, it retains susceptibility to cellular immunity. Here, we characterized vaccine-induced T cells specific for various SARS-CoV-2 variants and identified HLA-A*24:02-restricted CD8 + T cells that strongly suppressed Omicron BA.1 replication. Mutagenesis analyses revealed that a G446S mutation, located just outside the N-terminus of the cognate epitope, augmented TCR recognition of this variant. In contrast, no enhanced suppression of replication was observed against cells infected with the prototype, Omicron BA.2, and Delta variants that express G446. The enhancing effect of the G446S mutation was lost when target cells were treated with inhibitors of tripeptidyl peptidase II, a protein that mediates antigen processing. These results demonstrate that the G446S mutation in the Omicron BA.1 variant affects antigen processing/presentation and potentiates antiviral activity by vaccine-induced T cells, leading to enhanced T cell immunity towards emerging variants.

3.
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

4.
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
5.
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.

6.
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.

7.
Cell Rep ; 36(2): 109385, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1283972

ABSTRACT

Administration of convalescent plasma or neutralizing monoclonal antibodies (mAbs) is a potent therapeutic option for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 variants with mutations in the spike protein have emerged in many countries. To evaluate the efficacy of neutralizing antibodies induced in convalescent patients against emerging variants, we isolate anti-spike mAbs from two convalescent COVID-19 patients infected with prototypic SARS-CoV-2 by single-cell sorting of immunoglobulin-G-positive (IgG+) memory B cells. Anti-spike antibody induction is robust in these patients, and five mAbs have potent neutralizing activities. The efficacy of most neutralizing mAbs and convalescent plasma samples is maintained against B.1.1.7 and mink cluster 5 variants but is significantly decreased against variants B.1.351 from South Africa and P.1 from Brazil. However, mAbs with a high affinity for the receptor-binding domain remain effective against these neutralization-resistant variants. Rapid spread of these variants significantly impacts antibody-based therapies and vaccine strategies against SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/immunology , COVID-19/virology , Cell Line , HEK293 Cells , Humans , Immunization, Passive , Male , Mutation , Neutralization Tests , Protein Domains , Spike Glycoprotein, Coronavirus/genetics
8.
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
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