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Emergence of unique SARS-CoV-2 ORF10 variants and their impact on protein structure and function.

ABSTRACT: The devastating impact of the ongoing coronavirus disease 2019 (COVID-19) on public health, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has made targeting the COVID-19 pandemic a top priority in medical research and pharmaceutical development. Surveillance of SARS-CoV-2 mutations is essential for the comprehension of SARS-CoV-2 variant diversity and their impact on virulence and pathogenicity. The SARS-CoV-2 open reading frame 10 (ORF10) protein interacts with multiple human proteins CUL2, ELOB, ELOC, MAP7D1, PPT1, RBX1, THTPA, TIMM8B, and ZYG11B expressed in lung tissue. Mutations and co-occurring mutations in the emerging SARS-CoV-2 ORF10 variants are expected to impact the severity of the virus and its associated consequences. In this article, we highlight 128 single mutations and 35 co-occurring mutations in the unique SARS-CoV-2 ORF10 variants. The possible predicted effects of these mutations and co-occurring mutations on the secondary structure of ORF10 variants and host protein interactomes are presented. The findings highlight the possible effects of mutations and co-occurring mutations on the emerging 140 ORF10 unique variants from secondary structure and intrinsic protein disorder perspectives.

SUBMITTER: Hassan SS

PROVIDER: S-EPMC8635690 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionA key feature of the COVID-19 pandemic has been the emergence of SARS-CoV-2 variants with different transmission characteristics. However, when a novel variant arrives in a host population, it will not necessarily lead to many cases. Instead, it may fade out, due to stochastic effects and the level of immunity in the population. Immunity against novel SARS-CoV-2 variants may be influenced by prior exposures to related viruses, such as other SARS-CoV-2 variants and seasonal coronaviruses, and the level of cross-reactive immunity conferred by those exposures.MethodsHere, we investigate the impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants in a simplified scenario in which a novel SARS-CoV-2 variant is introduced after an antigenically related virus has spread in the population. We use mathematical modelling to explore the risk that the novel variant invades the population and causes a large number of cases, as opposed to fading out with few cases.ResultsWe find that, if cross-reactive immunity is complete (i.e. someone infected by the previously circulating virus is not susceptible to the novel variant), the novel variant must be more transmissible than the previous virus to invade the population. However, in a more realistic scenario in which cross-reactive immunity is partial, we show that it is possible for novel variants to invade, even if they are less transmissible than previously circulating viruses. This is because partial cross-reactive immunity effectively increases the pool of susceptible hosts that are available to the novel variant compared to complete cross-reactive immunity. Furthermore, if previous infection with the antigenically related virus assists the establishment of infection with the novel variant, as has been proposed following some experimental studies, then even variants with very limited transmissibility are able to invade the host population.DiscussionOur results highlight that fast assessment of the level of cross-reactive immunity conferred by related viruses against novel SARS-CoV-2 variants is an essential component of novel variant risk assessments.

Project description:Coronavirus disease 2019 (COVID-19) has emerged in December 2019 when the first case was reported in Wuhan, China and turned into a pandemic with 27 million (September 9th) cases. Currently, there are over 95,000 complete genome sequences of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, in public databases, accompanying a growing number of studies. Nevertheless, there is still much to learn about the viral population variation when the virus is evolving as it continues to spread. We have analyzed SARS-CoV-2 genomes to identify the most variant sites, as well as the stable, conserved ones in samples collected in the Netherlands until June 2020. We identified the most frequent mutations in different geographies. We also performed a phylogenetic study focused on the Netherlands to detect novel variants emerging in the late stages of the pandemic and forming local clusters. We investigated the S and N proteins on SARS-CoV-2 genomes in the Netherlands and found the most variant and stable sites to guide development of diagnostics assays and vaccines. We observed that while the SARS-CoV-2 genome has accumulated mutations, diverging from reference sequence, the variation landscape is dominated by four mutations globally, suggesting the current reference does not represent the virus samples circulating currently. In addition, we detected novel variants of SARS-CoV-2 almost unique to the Netherlands that form localized clusters and region-specific sub-populations indicating community spread. We explored SARS-CoV-2 variants in the Netherlands until June 2020 within a global context; our results provide insight into the viral population diversity for localized efforts in tracking the transmission of COVID-19, as well as sequenced-based approaches in diagnostics and therapeutics. We emphasize that little diversity is observed globally in recent samples despite the increased number of mutations relative to the established reference sequence. We suggest sequence-based analyses should opt for a consensus representation to adequately cover the genomic variation observed to speed up diagnostics and vaccine design.

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Emergence of unique SARS-CoV-2 ORF10 variants and their impact on protein structure and function.

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