Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

• Published in: bioRxiv
• Main Authors: Moll, Tobias, Odon, Valerie, Harvey, Calum, Collins, Mark O, Peden, Andrew, Franklin, John, Graves, Emily, Marshall, Jack N G, Souza, Cleide Dos Santos, Zhang, Sai, Azzouz, Mimoun, Gordon, David, Krogan, Nevan, Ferraiuolo, Laura, Snyder, Michael P, Shaw, Pamela J, Rehwinkel, Jan, Cooper-Knock, Johnathan
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 07.03.2022
• Subjects: Cell viability; Coronaviruses; COVID-19; CRISPR; DNA-directed RNA polymerase; Gene expression; Genomes; Immune response; Interferon; Morbidity; Proteins; Replication; RNA polymerase; Severe acute respiratory syndrome coronavirus 2; Statistical analysis; Therapeutic targets
• DOI: 10.1101/2022.03.06.483172

New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an association between increased expression of and higher risk of clinical COVID-19 which survived stringent multiple testing correction. EXOSC2 is a component of the RNA exosome and indeed, LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within in Calu-3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated oligoadenylate synthase ( genes, which have been linked to a successful immune response against SARS-CoV-2. Reduced EXOSC2 expression did not reduce cellular viability. OAS gene expression changes occurred independent of infection and in the absence of significant upregulation of other interferon-stimulated genes (ISGs). Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.