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1.
Nature ; 593(7857): 136-141, 2021 05.
Article in English | MEDLINE | ID: covidwho-2114170

ABSTRACT

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunization, Passive , Male , Middle Aged , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic/administration & dosage
3.
4.
Signal Transduct Target Ther ; 7(1): 241, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1937418

ABSTRACT

Recently, a large number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continuously emerged and posed a major threat to global public health. Among them, particularly, Omicron variant (B.1.1.529), first identified in November 2021, carried numerous mutations in its spike protein (S), and then quickly spread around the world. Currently, Omicron variant has expanded into more than one hundred sublineages, such as BA.1, BA.2, BA.2.12.1, BA.4 and BA.5, which have already become the globally dominant variants. Different from other variants of concern (VOCs) of SARS-CoV-2, the Omicron variant and its sublineages exhibit increased transmissibility and immune escape from neutralizing antibodies generated through previous infection or vaccination, and have caused numerous re-infections and breakthrough infections. In this prospective, we have focused on the origin, virological features, immune evasion and intervention of Omicron sublineages, which will benefit the development of next-generation vaccines and therapeutics, including pan-sarbecovirus and universal anti-CoV therapeutics, to combat currently circulating and future emerging Omicron sublineages as well as other SARS-CoV-2 variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Immune Evasion/genetics , Prospective Studies , SARS-CoV-2/genetics
5.
Signal Transduct Target Ther ; 7(1): 202, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1908146

ABSTRACT

The persistent COVID-19 pandemic since 2020 has brought an enormous public health burden to the global society and is accompanied by various evolution of the virus genome. The consistently emerging SARS-CoV-2 variants harboring critical mutations impact the molecular characteristics of viral proteins and display heterogeneous behaviors in immune evasion, transmissibility, and the clinical manifestation during infection, which differ each strain and endow them with distinguished features during populational spread. Several SARS-CoV-2 variants, identified as Variants of Concern (VOC) by the World Health Organization, challenged global efforts on COVID-19 control due to the rapid worldwide spread and enhanced immune evasion from current antibodies and vaccines. Moreover, the recent Omicron variant even exacerbated the global anxiety in the continuous pandemic. Its significant evasion from current medical treatment and disease control even highlights the necessity of combinatory investigation of the mutational pattern and influence of the mutations on viral dynamics against populational immunity, which would greatly facilitate drug and vaccine development and benefit the global public health policymaking. Hence in this review, we summarized the molecular characteristics, immune evasion, and impacts of the SARS-CoV-2 variants and focused on the parallel comparison of different variants in mutational profile, transmissibility and tropism alteration, treatment effectiveness, and clinical manifestations, in order to provide a comprehensive landscape for SARS-CoV-2 variant research.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/genetics , Humans , Immune Evasion/genetics , Pandemics , SARS-CoV-2/genetics
6.
J Virol ; 96(8): e0003722, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1779311

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose an enormous threat to economic activity and public health worldwide. Previous studies have shown that the nonstructural protein 5 (nsp5, also called 3C-like protease) of alpha- and deltacoronaviruses cleaves Q231 of the NF-κB essential modulator (NEMO), a key kinase in the RIG-I-like receptor pathway, to inhibit type I interferon (IFN) production. In this study, we found that both SARS-CoV-2 nsp5 and SARS-CoV nsp5 cleaved NEMO at multiple sites (E152, Q205, and Q231). Notably, SARS-CoV-2 nsp5 exhibited a stronger ability to cleave NEMO than SARS-CoV nsp5. Sequence and structural alignments suggested that an S/A polymorphism at position 46 of nsp5 in SARS-CoV versus SARS-CoV-2 may be responsible for this difference. Mutagenesis experiments showed that SARS-CoV-2 nsp5 (S46A) exhibited poorer cleavage of NEMO than SARS-CoV-2 nsp5 wild type (WT), while SARS-CoV nsp5 (A46S) showed enhanced NEMO cleavage compared with the WT protein. Purified recombinant SARS-CoV-2 nsp5 WT and SARS-CoV nsp5 (A46S) proteins exhibited higher hydrolysis efficiencies than SARS-CoV-2 nsp5 (S46A) and SARS-CoV nsp5 WT proteins in vitro. Furthermore, SARS-CoV-2 nsp5 exhibited stronger inhibition of Sendai virus (SEV)-induced interferon beta (IFN-ß) production than SARS-CoV-2 nsp5 (S46A), while introduction of the A46S substitution in SARS-CoV nsp5 enhanced suppression of SEV-induced IFN-ß production. Taken together, these data show that S46 is associated with the catalytic activity and IFN antagonism by SARS-CoV-2 nsp5. IMPORTANCE The nsp5-encoded 3C-like protease is the main coronavirus protease, playing a vital role in viral replication and immune evasion by cleaving viral polyproteins and host immune-related molecules. We showed that both SARS-CoV-2 nsp5 and SARS-CoV nsp5 cleave the NEMO at multiple sites (E152, Q205, and Q231). This specificity differs from NEMO cleavage by alpha- and deltacoronaviruses, demonstrating the distinct substrate recognition of SARS-CoV-2 and SARS-CoV nsp5. Compared with SARS-CoV nsp5, SARS-CoV-2 nsp5 encodes S instead of A at position 46. This substitution is associated with stronger catalytic activity, enhanced cleavage of NEMO, and increased interferon antagonism of SARS-CoV-2 nsp5. These data provide new insights into the pathogenesis and transmission of SARS-CoV-2.


Subject(s)
Coronavirus 3C Proteases , Interferon Type I , SARS Virus , SARS-CoV-2 , Antiviral Agents , COVID-19/immunology , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Humans , Immune Evasion/genetics , Interferon Type I/antagonists & inhibitors , Interferon Type I/metabolism , SARS Virus/enzymology , SARS Virus/genetics , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Virus Replication/genetics
7.
PLoS Comput Biol ; 18(2): e1009726, 2022 02.
Article in English | MEDLINE | ID: covidwho-1753172

ABSTRACT

The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.


Subject(s)
COVID-19 , Genome, Viral , Immune Evasion , Mutation , SARS-CoV-2 , COVID-19/immunology , COVID-19/virology , Epitopes/genetics , Epitopes/immunology , Gene Frequency , Genome, Viral/genetics , Genome, Viral/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Mutation/genetics , Mutation/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Proteins/genetics , Viral Proteins/immunology
8.
Nat Commun ; 13(1): 1214, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1730288

ABSTRACT

The omicron variant of SARS-CoV-2 has been spreading rapidly across the globe. The virus-surface spike protein plays a critical role in the cell entry and immune evasion of SARS-CoV-2. Here we determined the 3.0 Å cryo-EM structure of the omicron spike protein ectodomain. In contrast to the original strain of SARS-CoV-2 where the receptor-binding domain (RBD) of the spike protein takes a mixture of open ("standing up") and closed ("lying down") conformations, the omicron spike molecules are predominantly in the open conformation, with one upright RBD ready for receptor binding. The open conformation of the omicron spike is stabilized by enhanced inter-domain and inter-subunit packing, which involves new mutations in the omicron strain. Moreover, the omicron spike has undergone extensive mutations in RBD regions where known neutralizing antibodies target, allowing the omicron variant to escape immune surveillance aimed at the original viral strain. The stable open conformation of the omicron spike sheds light on the cell entry and immune evasion mechanisms of the omicron variant.


Subject(s)
COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/ultrastructure , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cryoelectron Microscopy , Humans , Immune Evasion/genetics , Models, Molecular , Mutation , Pandemics , Protein Conformation , Protein Domains/genetics , Protein Domains/immunology , Protein Interaction Domains and Motifs/genetics , Protein Interaction Domains and Motifs/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
9.
Nat Commun ; 13(1): 1152, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1730284

ABSTRACT

In spring 2021, an increasing number of infections was observed caused by the hitherto rarely described SARS-CoV-2 variant A.27 in south-west Germany. From December 2020 to June 2021 this lineage has been detected in 31 countries. Phylogeographic analyses of A.27 sequences obtained from national and international databases reveal a global spread of this lineage through multiple introductions from its inferred origin in Western Africa. Variant A.27 is characterized by a mutational pattern in the spike gene that includes the L18F, L452R and N501Y spike amino acid substitutions found in various variants of concern but lacks the globally dominant D614G. Neutralization assays demonstrate an escape of A.27 from convalescent and vaccine-elicited antibody-mediated immunity. Moreover, the therapeutic monoclonal antibody Bamlanivimab and partially the REGN-COV2 cocktail fail to block infection by A.27. Our data emphasize the need for continued global monitoring of novel lineages because of the independent evolution of new escape mutations.


Subject(s)
COVID-19/immunology , COVID-19/virology , Pandemics , SARS-CoV-2/immunology , Africa, Western/epidemiology , Amino Acid Substitution , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/immunology , Antiviral Agents/pharmacology , COVID-19/transmission , Drug Combinations , Germany/epidemiology , Global Health , Humans , Immune Evasion/genetics , Mutation , Phylogeography , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
10.
J Med Virol ; 94(4): 1738-1744, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1718408

ABSTRACT

As the latest identified novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC), the influence of Omicron on our globe grows promptly. Compared with the last VOC (Delta variant), more mutations were identified, which may address the characteristics of Omicron. Considering these crucial mutations and their implications including an increase in transmissibility, COVID-19 severity, and reduction of efficacy of currently available diagnostics, vaccines, and therapeutics, Omicron has been classified as one of the VOC. Notably, 15 of these mutations reside in the receptor-binding domain of spike glycoprotein, which may alter transmissibility, infectivity, neutralizing antibody escape, and vaccine breakthrough cases of COVID-19. Therefore, our present study characterizes the mutational hotspots of the Omicron variant in comparison with the Delta variant of SARS-CoV-2. Furthermore, detailed information was analyzed to characterize the global perspective of Omicron, including transmission dynamic, effect on testing, and immunity, which shall promote the progress of the clinical application and basic research. Collectively, our data suggest that due to continuous variation in the spike glycoprotein sequences, the use of coronavirus-specific attachment inhibitors may not be the current choice of therapy for emerging SARS-CoV-2 VOCs. Hence, we need to proceed with a sense of urgency in this matter.


Subject(s)
SARS-CoV-2/genetics , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/transmission , COVID-19 Testing , Humans , Immune Evasion/genetics , Mutation , Phylogeny , Prevalence , Protein Binding/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vaccination , Virus Attachment
11.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Article in English | MEDLINE | ID: covidwho-1684241

ABSTRACT

SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5' untranslated region (5' UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5' UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2-induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus' own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.


Subject(s)
5' Untranslated Regions/genetics , Immune Evasion/genetics , Protein Biosynthesis , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Animals , Base Sequence , Chlorocebus aethiops , HEK293 Cells , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immune Evasion/drug effects , Mice, Transgenic , Models, Biological , Oligonucleotides, Antisense/pharmacology , Protein Biosynthesis/drug effects , SARS-CoV-2/drug effects , Vero Cells , Virus Replication/drug effects
12.
Cell Rep Med ; 3(2): 100540, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1671308

ABSTRACT

It is unclear whether SARS-CoV-2 VOCs differentially escape Fc effector functions of antibodies in addition to neutralization. In this issue of Cell Reports Medicine, Richardson et al.1 show that VOCs differ both in their ability to evade as well as elicit cross-reactive Fc-effector functions.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Immune Evasion/genetics , Immunoglobulin Fc Fragments/immunology , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , COVID-19/virology , Cross Reactions , Humans , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
13.
Cell Rep ; 38(9): 110428, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1670282

ABSTRACT

The recently reported B.1.1.529 Omicron variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 34 mutations in the spike protein relative to the Wuhan strain, including 15 mutations in the receptor-binding domain (RBD). Functional studies have shown Omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here, we report a 3.1 Å-resolution cryoelectron microscopy (cryo-EM) structure of the Omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with high mobility of RBD. Many mutations cause steric clashes and/or altered interactions at antibody-binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the Omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies.


Subject(s)
Cryoelectron Microscopy , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Humans , Immune Evasion/genetics , Models, Molecular , Mutation , Neutralization Tests , Protein Binding , Protein Structure, Quaternary , SARS-CoV-2/genetics , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/genetics
14.
FEBS J ; 289(14): 4240-4250, 2022 07.
Article in English | MEDLINE | ID: covidwho-1666305

ABSTRACT

The SARS-CoV-2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS-CoV-2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor-binding domain (RBD) and in the N-terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS-CoV-2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.


Subject(s)
COVID-19 , Intrinsically Disordered Proteins , Humans , Immune Evasion/genetics , Intrinsically Disordered Proteins/genetics , Nucleoproteins , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism
15.
Phys Chem Chem Phys ; 24(5): 3410-3419, 2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1650366

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among all the potential targets studied for developing drugs and antibodies, the spike (S) protein is the most striking one, which is on the surface of the virus. In contrast with the intensively investigated immunodominant receptor-binding domain (RBD) of the protein, little is known about the neutralizing antibody binding mechanisms of the N-terminal domain (NTD), let alone the effects of NTD mutations on antibody binding and thereby the risk of immune evasion. Based on 400 ns molecular dynamics simulation for 11 NTD-antibody complexes together with other computational approaches in this study, we investigated critical residues for NTD-antibody binding and their detailed mechanisms. The results show that 36 residues on the NTD including R246, Y144, K147, Y248, L249 and P251 are critically involved in the direct interaction of the NTD with many monoclonal antibodies (mAbs), indicating that the viruses harboring these residue mutations may have a high risk of immune evasion. Binding free energy calculations and an interaction mechanism study reveal that R246I, which is present in the Beta (B.1.351/501Y.V2) variant, may have various impacts on current NTD antibodies through abolishing the hydrogen bonds and electrostatic interaction with the antibodies or affecting other interface residues. Therefore, special attention should be paid to the mutations of these key residues in future antibody and vaccine design and development.


Subject(s)
Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/metabolism , Immune Evasion/genetics , Mutation , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , Hydrogen Bonding , Molecular Dynamics Simulation , Protein Binding , Protein Domains/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Thermodynamics
16.
Cell Rep Med ; 3(2): 100527, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1649678

ABSTRACT

The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Mutation , Protein Domains/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , COVID-19/virology , Epitopes/genetics , Epitopes/immunology , Humans , Immune Evasion/genetics , Neutralization Tests , Protein Binding , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
17.
Front Immunol ; 12: 767726, 2021.
Article in English | MEDLINE | ID: covidwho-1639598

ABSTRACT

Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus-host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2. SCV2-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-2-5p play an important role in evasion of type I interferon response through targeting several genes in type I interferon signaling pathway. Particularly worth mentioning is that highly expressed SCV2-miR-ORF1ab-2-5p inhibits some key genes in the host innate immune response, such as IRF7, IRF9, STAT2, OAS1, and OAS2. SCV2-miR-ORF1ab-2-5p has also been found to mediate allelic differential expression of COVID-19-susceptible gene OAS1. In conclusion, these results suggest that SARS-CoV-2 uses its miRNAs to evade the type I interferon response and links the functional viral sequence to the susceptible genetic background of the host.


Subject(s)
Genetic Predisposition to Disease/genetics , Immune Evasion/genetics , Interferon Type I/genetics , SARS-CoV-2/genetics , 2',5'-Oligoadenylate Synthetase/genetics , COVID-19/pathology , Cell Line , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/immunology , Interferon Regulatory Factor-7/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/immunology , STAT2 Transcription Factor/genetics
18.
Nucleic Acids Res ; 50(3): 1551-1561, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1636373

ABSTRACT

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying variants of concern (VOC). Viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host single nucleotide variations (iSNVs). Analysing 1347 samples collected till June 2020, we recorded 16 410 iSNV sites throughout the SARS-CoV-2 genome. We found ∼42% of the iSNV sites to be reported as SNVs by 30 September 2020 in consensus sequences submitted to GISAID, which increased to ∼80% by 30th June 2021. Following this, analysis of another set of 1774 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) lineage-defining variations appeared as iSNVs before getting fixed in the population. Besides, mutations in RdRp as well as RNA-editing by APOBEC and ADAR deaminases seem to contribute to the differential prevalence of iSNVs in hosts. We also observe hyper-variability at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions.


Subject(s)
Evolution, Molecular , Genetic Variation/genetics , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/genetics , APOBEC-1 Deaminase/genetics , Adenosine Deaminase/genetics , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/genetics , Databases, Genetic , Immune Evasion/genetics , India/epidemiology , Phylogeny , RNA-Binding Proteins/genetics , SARS-CoV-2/classification , SARS-CoV-2/growth & development , Spike Glycoprotein, Coronavirus/genetics , Vero Cells
19.
Eur Rev Med Pharmacol Sci ; 25(24): 8019-8022, 2021 12.
Article in English | MEDLINE | ID: covidwho-1605687

ABSTRACT

Recently a new variant of SARS-CoV-2 was reported from South Africa. World Health Organization (WHO) named this mutant as a variant of concern - Omicron (B.1.1.529) on 26th November 2021. This variant exhibited more than thirty amino acid mutations in the spike protein. This mutation rate is exceeding the other variants by approximately 5-11 times in the receptor-binding motif of the spike protein. Omicron (B.1.1.529) variant might have enhanced transmissibility and immune evasion. This new variant can reinfect individuals previously infected with other SARS-CoV-2 variants. Scientists expressed their concern about the efficacy of already existing COVID-19 vaccines against Omicron (B.1.1.529) infections. Some of the crucial mutations that are detected in the receptor-binding domain of the Omicron variant have been shared by previously evolved SARS-CoV-2 variants. Based on the Omicron mutation profile in the receptor-binding domain and motif, it might have collectively enhanced or intermediary infectivity relative to its previous variants. Due to extensive mutations in the spike protein, the Omicron variant might evade the immunity in the vaccinated individuals.


Subject(s)
COVID-19/epidemiology , Reinfection/epidemiology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , COVID-19/immunology , COVID-19/transmission , COVID-19/virology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , Immune Evasion/genetics , Immunogenicity, Vaccine , Mutation , Reinfection/immunology , Reinfection/transmission , Reinfection/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Vaccine Potency
20.
Viruses ; 13(12)2021 12 19.
Article in English | MEDLINE | ID: covidwho-1580420

ABSTRACT

Rapid molecular surveillance of SARS-CoV-2 S-protein variants leading to immune escape and/or increased infectivity is of utmost importance. Among global bottlenecks for variant monitoring in diagnostic settings are sequencing and bioinformatics capacities. In this study, we aimed to establish a rapid and user-friendly protocol for high-throughput S-gene sequencing and subsequent automated identification of variants. We designed two new primer pairs to amplify only the immunodominant part of the S-gene for nanopore sequencing. Furthermore, we developed an automated "S-Protein-Typer" tool that analyzes and reports S-protein mutations on the amino acid level including a variant of concern indicator. Validation of our primer panel using SARS-CoV-2-positive respiratory specimens covering a broad Ct range showed successful amplification for 29/30 samples. Restriction to the region of interest freed sequencing capacity by a factor of 12-13, compared with whole-genome sequencing. Using either the MinION or Flongle flow cell, our sequencing strategy reduced the time required to identify SARS-CoV-2 variants accordingly. The S-Protein-Typer tool identified all mutations correctly when challenged with our sequenced samples and 50 deposited sequences covering all VOCs (December 2021). Our proposed S-protein variant screening offers a simple, more rapid, and low-cost entry into NGS-based SARS-CoV-2 analysis, compared with current whole-genome approaches.


Subject(s)
High-Throughput Nucleotide Sequencing/methods , Nanopore Sequencing/methods , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , COVID-19/epidemiology , COVID-19/virology , Epidemiological Monitoring , Genotype , Humans , Immune Evasion/genetics , Mutation , SARS-CoV-2/immunology
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