Dataset Information

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.

ABSTRACT:

Objectives

More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.

Methods

A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.

Results

A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.

Conclusions

This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

SUBMITTER: Loucera C

PROVIDER: S-EPMC9500738 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.

Loucera Carlos C Perez-Florido Javier J Casimiro-Soriguer Carlos S CS Ortuño Francisco M FM Carmona Rosario R Bostelmann Gerrit G Martínez-González L Javier LJ Muñoyerro-Muñiz Dolores D Villegas Román R Rodriguez-Baño Jesus J Romero-Gomez Manuel M Lorusso Nicola N Garcia-León Javier J Navarro-Marí Jose M JM Camacho-Martinez Pedro P Merino-Diaz Laura L Salazar Adolfo de A Viñuela Laura L The Andalusian Covid-Sequencing Initiative Lepe Jose A JA Garcia Federico F Dopazo Joaquin J

Viruses 20220827 9

<h4>Objectives</h4>More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.<h4>Methods</h4>A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.<h4>Resul ...[more]

PMID: 36146700

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Project description:BackgroundA large number of mutations in the Spike (S) protein of the SARS-CoV-2 omicron variant have been noted to alter the receptor binding domain (RBD) and increase the binding surface and enhance the opening of the binding pocket. The cumulative effect of S1 and S2 subunit mutations can influence the conformational dynamics of the binding surface, facilitating the release of viral genome into host cells.AimThis study investigates the deleterious mutations across all Omicron lineages identified in our analysis and their effect on the conformational stability of RBD opening.MethodsWhole Genome Sequencing of 231 SARS-CoV-2 positive patients in Karachi, Pakistan, were performed using Illumina Miseq instrument and raw reads were analyzed using viralrecon pipeline. The mutational effects of omicron variant on the stability of S protein, including wild-type (7FG7), close (6VXX) and open (6VYB) states, were assessed through MD simulations.ResultsFour deleterious missense mutations (Tyr505His, Asn764Lys, Asp950Asn, Asn969Lys) were identified in the S1 and S2 subunit of the S protein of omicron variant. In the wildtype and open state mutant models, Tyr505His, Asp950Asn and Asn969Lys caused destabilizing effects, higher RMSDs vs. wild-type, and fluctuations in the RBD (438-510) region and S2 subunit (946-1010), compared to the native structure. These mutations increased the binding pocket propensity to open in mutant model compared to the native open conformation (6VYB). This structural change promoted trimer opening in the open state through α-helix movement in the S2 subunit away from the RBD region. In the closed state, only S2 subunit mutations (Asp950Asn and Asn969Lys) lead to predicted destabilization through the movement of protomer C towards protomer B (RBD region). These S2 subunit mutations are predicted to stabilize the RBD "down" conformation potentially enhancing spike antigenic heterogeneity.ConclusionThis study highlighted the cumulative effect of S1 (Tyr505His) and S2 (Asp950Asn and Asn969Lys) subunits mutations on different S protein states, potentially controlling its conformational dynamics and presentation to host receptors. Future experimental studies are needed to elucidate the biological significance of these alterations, particularly by establishing a link between the identified mutations and their impact on viral biology.

Project description:The emergence and evolution of SARS-CoV-2 is characterized by the occurrence of diverse sets of mutations that affect virus characteristics, including transmissibility and antigenicity. Recent studies have focused mostly on spike protein mutations; however, SARS-CoV-2 variants of interest (VoI) or concern (VoC) contain significant mutations in the nucleocapsid protein as well. To study the relevance of mutations at the virion level, recombinant baculovirus expression system-based virus-like particles (VLPs) were generated for the prototype Wuhan sequence along with spike protein mutants like D614G and G1124V and the significant RG203KR mutation in nucleocapsid. All four structural proteins were assembled in a particle for which the morphology and size, confirmed by transmission electron microscopy, closely resembled that of the native virion. The VLP harboring RG203KR mutations in nucleocapsid exhibited augmentation of humoral immune responses and enhanced neutralization by immunized mouse sera. Results demonstrate a noninfectious platform to quickly assess the implication of mutations in structural proteins of the emerging variant. IMPORTANCE Since its origin in late 2019, the SARS-CoV-2 virus has been constantly mutating and evolving. Current studies mostly employ spike protein (S) pseudovirus systems to determine the effects of mutations on the infectivity and immunogenicity of variants. Despite its functional importance and emergence as a mutational hot spot, the nucleocapsid (N) protein has not been widely studied. The generation of SARS-CoV-2 VLPs in a baculoviral system in this study, with mutations in the S and N proteins, allowed examination of the involvement of all the structural proteins involved in viral entry and eliciting an immune response. This approach provides a platform to study the effect of mutations in structural proteins of SARS-CoV-2 that potentially contribute to cell infectivity, immune response, and immune evasion, bypassing the use of infectious virus for the same analyses.

Dataset Information

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.

Objectives

Methods

Results

Conclusions

Publications

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.

Similar Datasets

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