SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression

Nemudryi, Artem; Nemudraia, Anna; Wiegand, Tanner; Nichols, Joseph; Snyder, Deann T.; Hedges, Jodi F.; Cicha, Calvin; Lee, Helen H.; Vanderwood, Karl K.; Bimczok, Diane; Jutila, Mark A.; Wiedenheft, Blake

doi:10.1016/j.celrep.2021.109197

Cited by 75 publications

(96 citation statements)

References 76 publications

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“…Interestingly, several independent studies have reported SARS-CoV-2 isolates with unique in-and out-of-frame deletions in Orf7a resulting in heavily truncated and/or non functional polypeptides 28,29 . Although the implications of these mutations are not completely understood at present, we observe that more recently, depletion of Orf7a has been linked with reduced inactivation of the host immune system by SARS-CoV-2 30 . Globally, the 26 aforementioned lineages associated with multiple HGs include about 67%…”

Section: Functional Evaluation Of High Frequency Variants Fixed In Distinct Hgsmentioning

confidence: 75%

“…Our finding that approximately 9% of all current SARS-CoV-2 isolates in the B.1.1.7 lineage carry a truncated form of the orf7A protein is also particularly relevant. Indeed, orf7a was recently shown to inhibit IFN-I signaling 30 while genetic defects in IFN-I signaling in the host have been recently linked with more severe forms of COVID-19 36 . Taken all together these observations might suggest again the potential emergence of less pathogenic/attenuated strains in B.1.1.7.…”

Section: Discussionmentioning

confidence: 99%

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Unsupervised classification of SARS-CoV-2 genomic sequences uncovers hidden genetic diversity and suggests an efficient strategy for genomic surveillance

Chiara

Horner

Ferrandi

et al. 2021

Preprint

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Accurate and timely monitoring of emerging genomic diversity is crucial for limiting the spread of potentially more transmissible/pathogenic strains of SARS-CoV-2. At the time of writing, over 1.8M distinct viral genome sequences have been made publicly available, and a sophisticated nomenclature system based on phylogenetic evidence and expert manual curation has allowed the relatively rapid classification of emerging lineages of potential concern. Here, we propose a complementary approach that integrates fine-grained spatiotemporal estimates of allele frequency with unsupervised clustering of viral haplotypes, and demonstrate that multiple highly frequent genetic variants, arising within large and/or rapidly expanding SARS-CoV-2 lineages, have highly biased geographic distributions and are not adequately captured by current SARS-CoV-2 nomenclature standards. Our results advocate a partial revision of current methods used to track SARS-CoV-2 genomic diversity and highlight the importance of the application of strategies based on the systematic analysis and integration of regional data. Here we provide a complementary, completely automated and reproducible framework for the mapping of genetic diversity in time and across different geographic regions, and for the prioritization of virus variants of potential concern. We believe that the approach outlined in this study will contribute to relevant advances to current genomic surveillance methods.

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Section: Functional Evaluation Of High Frequency Variants Fixed In Distinct Hgsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Unsupervised classification of SARS-CoV-2 genomic sequences uncovers hidden genetic diversity and suggests an efficient strategy for genomic surveillance

Chiara

Horner

Ferrandi

et al. 2021

Preprint

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“…In the SARS-CoV-2 genome, mutations distribute over genes coding basic structural proteins of the virus and ORFs (open reading frames) [ 36 , 37 , 38 ]. ORFs are defined as contiguous stretches with a start and a stop codon and a ‘protein-coding’ meaning, i.e., translation into a functional protein that contributes to viral transmission, replication, immune avoidance or overall fitness or that can encode an antigen detectable by the immune system or a diagnostic test [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

The Evolving Faces of the SARS-CoV-2 Genome

Schmidt

Arshad

Bernhart

et al. 2021

Viruses

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Surveillance of the evolving SARS-COV-2 genome combined with epidemiological monitoring and emerging vaccination became paramount tasks to control the pandemic which is rapidly changing in time and space. Genomic surveillance must combine generation and sharing sequence data with appropriate bioinformatics monitoring and analysis methods. We applied molecular portrayal using self-organizing maps machine learning (SOM portrayal) to characterize the diversity of the virus genomes, their mutual relatedness and development since the beginning of the pandemic. The genetic landscape obtained visualizes the relevant mutations in a lineage-specific fashion and provides developmental paths in genetic state space from early lineages towards the variants of concern alpha, beta, gamma and delta. The different genes of the virus have specific footprints in the landscape reflecting their biological impact. SOM portrayal provides a novel option for ‘bioinformatics surveillance’ of the pandemic, with strong odds regarding visualization, intuitive perception and ‘personalization’ of the mutational patterns of the virus genomes.

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“…ORF7A is a type 1 transmembrane protein and it has numerous putative functions involved in host-pathogen interactions and immune evasion (Nemudryi et al, 2021). ORF7A truncations in SARS-CoV-2 isolates have been discovered before, possibly associated with reduced capacity to subvert the innate immune response (Nemudryi et al, 2021). However, the previous work was carried out using non-clinically relevant cell models, such as Vero or HEK-derived lines.…”

Section: Phenotypic Differences Between Sars-cov-2 'Phe' and 'Bt201' P4mentioning

confidence: 99%

“…The mutations T4685I arose with P812R possibly suggesting genetic linkage, although this remains to be determined.It is of interest that BT20.1 carries a deletion in ORF7A that results in a frameshift and C-terminal truncation of the protein, likely ablating the transmembrane domain and tail. ORF7A is a type 1 transmembrane protein and it has numerous putative functions involved in host-pathogen interactions and immune evasion(Nemudryi et al, 2021). ORF7A truncations in SARS-CoV-2 isolates have been discovered before, possibly associated with reduced capacity to subvert the innate immune response(Nemudryi et al, 2021).…”

mentioning

confidence: 99%

Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution

Bamford

Broadbent

Aranday-Cortés

et al. 2021

Preprint

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SARS-CoV-2 continues to evolve, resulting in several variants of concern with novel properties. The factors driving SARS-CoV-2 fitness and evolution in the human respiratory tract remain poorly defined. Here, we provide evidence that both viral and host factors co-operate to shape SARS-CoV-2 genotypic and phenotypic change. Through viral whole genome sequencing, we explored the evolution of two clinical isolates of SARS CoV-2 during passage in unmodified Vero-derived cell lines and in parallel, in well-differentiated primary nasal epithelial cell (WD-PNEC) cultures. We identify a consistent, rich genetic diversity arising in vitro, variants of which could rapidly rise to near-fixation with 2 passages. Within isolates, SARS-CoV-2 evolution was dependent on host cells, with Vero-derived cells facilitating more profound genetic changes. However, most mutations were not shared between strains. Furthermore, comparison of both Vero-grown isolates on WD-PNECs disclosed marked growth attenuation mapping to the loss of the polybasic cleavage site (PBCS) in Spike while the strain with mutations in NSP12 (T293I), Spike (P812R) and a truncation of ORF7a remained viable in WD-PNECs. Our work highlights the significant genetic plasticity of SARS-CoV-2 while uncovering an influential role for collaboration between viral and host cell factors in shaping viral evolution and fitness in human respiratory epithelium.

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SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression

Cited by 75 publications

References 76 publications

Unsupervised classification of SARS-CoV-2 genomic sequences uncovers hidden genetic diversity and suggests an efficient strategy for genomic surveillance

Unsupervised classification of SARS-CoV-2 genomic sequences uncovers hidden genetic diversity and suggests an efficient strategy for genomic surveillance

The Evolving Faces of the SARS-CoV-2 Genome

Collaboration Between Host and Viral Factors Shape SARS-CoV-2 Evolution

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