Dataset Information

Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene.

ABSTRACT: The new SARS-CoV-2 poses a significant threat to human health but many aspects of its basic biology remain unknown. Its genome encodes accessory genes that differ significantly within coronaviruses and contribute to the virus pathogenicity. Among accessory genes, open reading frame 8 (ORF8) stands out by being highly variable and showing structural changes suspected to be related with the virus ability to spread. However, the function of ORF8 remains to be elucidated, making it less studied than other SARS-CoV-2 genes. Here I show that ORF8 is poorly conserved among related coronaviruses. The ORF8 phylogeny built using 11,113 SARS-CoV-2 sequences revealed traces of a typical expanding population with a small number of highly frequent lineages. Interestingly, I detected several nonsense mutations and three main deletions in the ORF8 gene that either remove or significantly change the ORF8 protein. These findings suggest that SARS-CoV-2 can persist without a functional ORF8 protein. Deletion breakpoints were found located in predicted hairpins suggesting a possible involvement of these elements in the rearrangement process. Although the function of ORF8 remains to be elucidated, its structural plasticity and high diversity suggest an important role in SARS-CoV-2 pathogenicity.

SUBMITTER: Pereira F

PROVIDER: S-EPMC7467077 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene.

Pereira Filipe F

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 20200902

The new SARS-CoV-2 poses a significant threat to human health but many aspects of its basic biology remain unknown. Its genome encodes accessory genes that differ significantly within coronaviruses and contribute to the virus pathogenicity. Among accessory genes, open reading frame 8 (ORF8) stands out by being highly variable and showing structural changes suspected to be related with the virus ability to spread. However, the function of ORF8 remains to be elucidated, making it less studied than ...[more]

PMID: 32890763

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Project description:As the world continues to fight the coronavirus pandemic caused by SARS‐CoV‐2, we are gaining valuable insights by comparing this virus to other human coronaviruses such as SARS‐CoV and MERS‐CoV that have also caused outbreaks. Coronaviruses infect many animal species, but disease severity varies between strains. Viral accessory proteins are generally implicated in increased infectivity, pathogenicity, and virulence. The accessory protein open reading frame 8 (ORF8), although not essential for viral replication, appears to play a critical role in disease severity by inhibiting multiple pathways of the immune response. Furthermore, the ORF8 gene is found within a highly variable portion of the genome, increasing the possibility of dangerous mutant forms arising. Structure‐based design of therapeutics holds great promise for effective targeting of such rapidly evolving threats. Thus, we designed physical models and computer representations of ORF8, based on the published structure 7JTL, to better evaluate the structural features responsible for viral pathogenicity. ORF8 exists as a homodimer held together by amino acid residues that interact through hydrophobic interactions, hydrogen bonding, a salt bridge, and a disulfide bond. These interactions occur in a region referred to as the covalent interface. Another interface, referred to as the noncovalent interface, exists between separate homodimers and results in oligomerization. The homodimers in the oligomer are held together by an intermolecular beta sheet that is stabilized by an extensive hydrophobic surface. These two dimerization interfaces are unique to SARS‐CoV‐2 and have been proposed to be involved in the protein's ability to evade and suppress the host immune response. The computer and physical representations allow for better visualization of the ORF8 structure to evaluate the role of the multimeric structure. ORF8 has been found to interact with various host proteins, including Interleukin‐17 Receptor A (IL17RA), a pro‐inflammatory cytokine. To further corroborate the existence of this interaction and to better understand the role oligomerization might play in pathogenicity, we assessed the possible interactions of ORF8 (7JTL) and IL17RA (5N9B) through theoretical modeling using available tools such as HDOCK. A better understanding of these inter‐subunit interactions may improve our understanding of the unique mechanism the virus uses to evade the immune system and may be instrumental in the development of effective therapeutics.

Project description:The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against SARS-CoV-2, the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the Spike protein. Although these differences in Spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome which may affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other non-spike mutations on SARS-CoV-2 pathogenesis, we synthesized viruses where the WA1 Spike is replaced by each variant spike genes in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to the full variant viruses. Our work has revealed that non-spike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host and can lead to attenuating phenotypes in circulating variants of concern. This work suggests that while Spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may lead to less clinical disease, extended time toward knowing an infection exists in a person and thus increased time for transmission to occur.SignificanceA hallmark of the COVID19 pandemic has been the emergence of SARS-CoV-2 variants that have increased transmission and immune evasion. Each variant has a set of mutations that can be tracked by sequencing but little is known about their affect on pathogenesis. In this work we first identify accessory genes that are responsible for pathogenesis in vivo as well as identify the role of variant spike genes on replication and disease in mice. Isolating the role of Spike mutations in variants identifies the non-Spike mutations as key drivers of disease for each variant leading to the hypothesis that viral fitness depends on balancing increased Spike binding and immuno-evasion with attenuating phenotypes in other genes in the SARS-CoV-2 genome.

Dataset Information

Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene.

Publications

Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene.

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