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Whole blood transcriptome analysis reveals SARS-CoV-2 ORF8 as a potential therapeutic and vaccine target

ABSTRACT: The open reading frame (ORF) 8 in severe acute respiratory syndrome coronaviruses (SARS-CoVs), associated with host adaptation and viral replication, is a hotspot for mutation. However, mutation effects on host immune responses remain unknown. Here, whole blood transcriptomics performed on patients infected with mutant SARS-CoV-2 (Δ382; 382-nt deletion in ORF8) show differing profiles from wildtype SARS-CoV-2. Understanding the Δ382 mechanism and effects would allow for a focused approach in vaccine and antiviral development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155454 | GEO | 2021/04/24

REPOSITORIES: GEO

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Project description:SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cell’s ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

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Whole blood transcriptome analysis reveals SARS-CoV-2 ORF8 as a potential therapeutic and vaccine target

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