SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

Beaudoin-Bussières, Guillaume; Arduini, Ariana; Bourassa, Catherine; Medjahed, Halima; Gendron‐Lepage, Gabrielle; Richard, Jonathan; Pan, Qinghua; Wang, Zhen; Liang, Chen; Uchil, Pradeep D.

doi:10.1101/2022.03.30.486403

Cited by 6 publications

(2 citation statements)

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“…There are also reports that ORF8 modulates vesicular traffic through the unfolded protein response and, therefore, ER stress by stimulating the ATF6 and IRE1 pathways through the upregulation of the GRP78 and GRP94 chaperones [27]. Another small corona virus protein ORF9b interacted with Tom70 mitochondrial chaperone as revealed by cryo-electron microscopy [28]. Similarly, study indicated ORF3a also has trans activator function interacting MHC molecules [29].…”

Section: Resultsmentioning

confidence: 87%

SARS-CoV-2 ORF8 gene CAA=TAA and AAA=TAA Termination Codon Mutations found mostly in B.1.1.7 Variants was Independent of Popular L84S Point Mutations

2022

IJCMER

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Five VOCs of SARS-CoV-2 mainly caused million deaths worldwide and named as B.1.1.7 (U.K.), B.1.351 (South Africa), P.1 (Brazil), B.1.617.2 (India), and B.1.1.529 (Africa). In HIV mediated pathogenesis, small trans activator proteins (TAT, NEF, REV) modulate transcription of cellular genes. Similarly, preliminary reports indicated that corona virus ORF8 protein acts as histone mimics disrupting chromatic structure with many epigenetic changes and immune modulator functions. ORF8 protein had also some similarities to immunoglobulin domains and inhibited HMC-1 and IFN-beta functions. During evolution a 382-nucleotide deletion (∆382) in the ORF8 region of the corona virus genome leads to weak virus load and weak pathogenicity (accession no.MT374101). We BLAST searched deletion boundary and was selected few ORF8 protein truncated mutants. The C>T base change at 27972nt and another A>T base change at 28095nt created two termination codons (CAA=TAA and AAA=TAA) to produce 26AA and 67AA long ORF8 truncated proteins. Similar Blast-N search with oligonucleotides selected at the mutation boundaries gave many ORF8 mutants with distinct S24L, V32L, P38S, R52I, A65V, Y73C, L84S, K92E and V100L mutations with or without TAA termination mutations. Major mutations found in B.1.1.7 lineage which had spike 69HV and 145Y mutations and ORF1ab polyprotein 3675KSF deletion. However, one ORF8 mutant (accession no. OW221449) belongs to Omicron BA.2 variant with 24LPP spike deletion and others to Omicron BA.5 variants (accession nos. OP733645 and OP671680) with 24LPP and 69HV deletion in the spike protein. One termination codon mutant (accession no. OP711842) has also 63nt ORF7a/b deletions. Mutation did not change the hairpin structure in the ORF8 gene and ORF8 protein formed dimeric stable globular 3-D structure to interact with many host proteins. Clearly, generation of such abundant B.1.1.7 lineage ORF8 protein truncated mutants may be one of the causes for the extinction of Alpha variant of corona virus in 2021. Roles of ORF8 mutants as host proteins modulator were explained in light of other deletions and mutations in corona virus genome.

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Section: Resultsmentioning

confidence: 87%

SARS-CoV-2 ORF8 gene CAA=TAA and AAA=TAA Termination Codon Mutations found mostly in B.1.1.7 Variants was Independent of Popular L84S Point Mutations

2022

IJCMER

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Section: Resultsmentioning

confidence: 87%

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2022

IJCMER

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In HIV mediated pathogenesis, small trans activator proteins (TAT, NEF, REV) modulate transcription of cellular genes. Similarly, preliminary reports indicated that corona virus ORF8 protein acts as histone mimics disrupting chromatic structure with many epigenetic changes and immune modulator functions. ORF8 protein had also some similarities to immunoglobulin domains and inhibited HMC-1 and IFN-beta functions.During evolution a 382-nucleotide deletion (∆382) in the ORF8 region of the corona virus genome leads to weak virus load and weak pathogenicity (accession no.MT374101). We BLAST searched deletion boundary and was selected few ORF8 protein truncated mutants. The C>T base change at 27972nt and another A>T base change at 28095nt created two termination codons (CAA=TAA and AAA=TAA) to produce 26AA and 67AA long ORF8 truncated proteins. Similar Blast-N search with oligonucleotides selected at the mutation boundaries gave many ORF8 mutants with distinct S24L, V32L, P38S, R52I, A65V, Y73C, L84S, K92E and V100L mutations with or without TAA termination mutations.Major mutations found in B.1.1.7 lineage which had spike 69HV and 145Y mutations and ORF1ab polyprotein 3675KSF deletion. However, one ORF8 mutant (accession no. OW221449) belongs to Omicron BA.2 variant with 24LPP spike deletion and others to Omicron BA.5 variants (accession nos. OP733645 and OP671680) with 24LPP and 69HV deletion in the spike protein. One termination codon mutant (accession no. OP711842) has also 63nt ORF7a/b deletions. Mutation did not change the hairpin structure in the ORF8 gene and ORF8 protein formed dimeric stable globular 3-D structure to interact with many host proteins. Clearly, generation of such abundant B.1.1.7 lineage ORF8 protein truncated mutants may be one of the causes for the extinction of Alpha variant of corona virus in 2021. Roles of ORF8 mutants as host proteins modulator were explained in light of other deletions and mutations in corona virus genome.

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High fusion and cytopathy of SARS-CoV-2 variant B.1.640.1

Bolland,

Michel,

Planas

et al. 2023

Preprint

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SARS-CoV-2 variants with undetermined properties have emerged intermittently throughout the COVID-19 pandemic. Some variants possess unique phenotypes and mutations which allow further characterization of viral evolution and spike functions. Around 1100 cases of the B.1.640.1 variant were reported in Africa and Europe between 2021 and 2022, before the expansion of Omicron. Here, we analyzed the biological properties of a B.1.640.1 isolate and its spike. Compared to the ancestral spike, B.1.640.1 carried 14 amino acid substitutions and deletions. B.1.640.1 escaped binding by some anti-NTD and -RBD monoclonal antibodies, and neutralization by sera from convalescent and vaccinated individuals. In cell lines, infection generated large syncytia and a high cytopathic effect. In primary airway cells, B.1.640.1 replicated less than Omicron BA.1 and triggered more syncytia and cell death than other variants. The B.1.640.1 spike was highly fusogenic when expressed alone. This was mediated by two poorly characterized and infrequent mutations located in the spike S2 domain, T859N and D936H. Altogether, our results highlight the cytopathy of a hyper-fusogenic SARS-CoV-2 variant, supplanted upon the emergence of Omicron BA.1.ImportanceOur results highlight the plasticity of SARS-CoV-2 spike to generate highly fusogenic and cytopathic strains with the causative mutations being uncharacterized in previous variants. We describe mechanisms regulating the formation of syncytia and the subsequent consequences in cell lines and a primary culture model, which are poorly understood.

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SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

Cited by 6 publications

References 33 publications

SARS-CoV-2 ORF8 gene CAA=TAA and AAA=TAA Termination Codon Mutations found mostly in B.1.1.7 Variants was Independent of Popular L84S Point Mutations

SARS-CoV-2 ORF8 gene CAA=TAA and AAA=TAA Termination Codon Mutations found mostly in B.1.1.7 Variants was Independent of Popular L84S Point Mutations

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High fusion and cytopathy of SARS-CoV-2 variant B.1.640.1

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