SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load

Mourier, Tobias; Shuaib, Muhammad; Hala, Sharif; Mfarrej, Sara; Alofi, Fadwa S.; Naeem, Raeece; Alsomali, Afrah; Jorgensen, David A.; Subudhi, Amit Kumar; Rached, Fathia Ben; Guan, Qingtian; Salunke, Rahul; Ooi, Amanda Siok Lee; Esau, Luke; Douvropoulou, Olga; Nugmanova, Raushan; Perumal, Sadhasivam; Zhang, Huoming; Rajan, Issaac; Al‐Omari, Awad; Salih, Samer; Shamsan, Abbas; Mutair, Abbas Al; Taha, Jumana; Alahmadi, Abdulaziz; Khotani, Nashwa; Alhamss, Abdelrahman; Mahmoud, Ahmad Bakur; Alquthami, Khaled; Dageeg, Abdullah; Khogeer, Asim; Hashem, Anwar M.; Moraga, Paula; Volz, Erik; Almontashiri, Naif A M; Pain, Arnab

doi:10.1038/s41467-022-28287-8

Cited by 47 publications

(54 citation statements)

References 86 publications

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“…In total, 37 SARS-CoV-2 isolates had 5’-UTR-derived sequences in their N gene, in contrast to ∼336,000 isolates with either R203K or G204K as per NCBI Virus (mutations in SARS-CoV-2 SRA data); most were isolates of the variant of concern gamma GR/501Yv3 (P1) lineage (first detected in Brazil and Japan) from Brazil, Chile, and Peru, but also alpha (B.1.1.7; first detected in Great Britain) from USA and Canada (Supplemental legend to Figure 4). The R203K/G204R co-mutation has been associated with B.1.1.7 (alpha) lineage emergence, which along with variants with the co-mutation including the P1 (gamma) lineage (Franco-Muñoz et al 2020), possess a replication advantage over the preceding lineages and show increased nucleocapsid phosphorylation, infectivity, replication, virulence, fitness, and pathogenesis as documented in a hamster model, human cells, and COVID-19 patients including an analysis of association between COVID-19 severity and sample frequency of R203K/G204R co-mutations (Johnson et al 2021; Mourier et al 2022; Wu et al 2021).…”

Section: Resultsmentioning

confidence: 99%

Intragenomic rearrangements of SARS-CoV-2 and other β-coronaviruses

Patarca

Haseltine

2022

Preprint

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The continuation of the SARS-CoV-2 pandemic depends on the generation of new viral variants. Documented variation includes point mutations, deletions, insertions, and recombination among closely or distantly related coronaviruses. Here, we describe yet another aspect of genome variation by β-coronaviruses, including SARS-CoV-2. Specifically, we report numerous genomic insertions of 5′-untranslated region sequences into coding regions of SARS-CoV-2 and other beta-coronaviruses. To our knowledge this is the first systematic description of such insertions. In many cases, these insertions change viral protein sequences and further foster genomic flexibility and viral adaptability through insertion of transcription regulatory sequences in novel positions within the genome. Among human Embecorivus β-coronaviruses, for instance, from one-third to one-half of surveyed sequences in publicly available databases contain 5′-UTR-derived inserted sequences. In limited instances, there is mounting evidence that these insertions alter the fundamental biological properties of mutant viruses. Intragenomic rearrangements add to our appreciation of how SARS-CoV-2 variants may arise.

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Section: Resultsmentioning

confidence: 99%

Intragenomic rearrangements of SARS-CoV-2 and other β-coronaviruses

Patarca

Haseltine

2022

Preprint

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“…Earlier examinations of emerging mutations in N proteins (6, 14, 61–63), going back to June 2020, were necessarily more limited in scope, and while sufficient to examine hot spots and identify key replacements such as R203K/G204R (6, 10, 14, 64), it was not yet possible to draw conclusions from a survey of the entire mutational landscape. Due to the orders of magnitude larger coverage that has become available through the global genomic epidemiology efforts since then, we believe that the observed data now approaches the limits of possible mutations for functioning N-protein, and therefore reflects its biophysical properties.…”

Section: Discussionmentioning

confidence: 99%

“…A persistent concern is viral escape through evolution of therapeutic and immunological targets. Most attention in this regard is devoted to the viral spike protein that facilitates viral entry (6,7), though recent data additionally point to the importance of viral packaging by the nucleocapsid (N) protein modulating viral loads and thereby infectivity (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein

Zhao

Nguyen

et al. 2022

Preprint

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Worldwide SARS-CoV-2 sequencing efforts track emerging mutations in its spike protein, as well as characteristic mutations in other viral proteins. Besides their epidemiological importance, the observed SARS-CoV-2 sequences present an ensemble of viable protein variants, and thereby a source of information on viral protein structure and function. Charting the mutational landscape of the nucleocapsid (N) protein that facilitates viral assembly, we observe variability exceeding that of the spike protein, with more than 86% of residues that can be substituted, on average by 3-4 different amino acids. However, mutations exhibit an uneven distribution that tracks known structural features but also reveals highly protected stretches of unknown function. One of these conserved regions is in the central disordered linker proximal to the N-G215C mutation that has become dominant in the Delta variant, outcompeting G215 variants without further spike or N-protein substitutions. Structural models suggest that the G215C mutation stabilizes conserved transient helices in the disordered linker serving as protein-protein interaction interfaces. Comparing Delta variant N-protein to its ancestral version in biophysical experiments, we find a significantly more compact and less disordered structure. N-G215C exhibits substantially stronger self-association, shifting the unliganded protein from a dimeric to a tetrameric oligomeric state, which leads to enhanced co-assembly with nucleic acids. This suggests that the sequence variability of N-protein is mirrored by high plasticity of N-protein biophysical properties, which we hypothesize can be exploited by SARS-CoV-2 to achieve greater efficiency of viral assembly, and thereby enhanced infectivity.

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“…The R203K(Arginine→Lysine)+G204R(Glycine→Arginine) substitutions occur most frequently during N protein evolution [ 86 ]. The mutations together show more significant inhibition of RNA-induced interferon expression, and they can increase SARS-CoV-2 replication, pathogenicity, and fitness by modulating host-virus interactions [ 87 , 88 ].…”

Section: Structural Proteinsmentioning

confidence: 99%