SARS-CoV-2 Variants Show Different Host Cell Proteome Profiles With Delayed Immune Response Activation in Omicron-Infected Cells

• Published in: Molecular & cellular proteomics 2023-05, Vol.22 (5), p.100537-100537, Article 100537
• Main Authors: Metzler, Melinda, Tharyan, Rebecca George, Klann, Kevin, Grikscheit, Katharina, Bojkova, Denisa, Cinatl, Jindrich, Tascher, Georg, Ciesek, Sandra, Münch, Christian
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing; Antiviral Agents; COVID-19; Humans; Interferon; IRF-3; NF-kB; Omicron; Pandemics; Protein-translocation; Proteome; Proteomics; SARS-CoV-2
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1016/j.mcpro.2023.100537

The ancestral SARS-CoV-2 strain that initiated the Covid-19 pandemic at the end of 2019 has rapidly mutated into multiple variants of concern with variable pathogenicity and increasing immune escape strategies. However, differences in host cellular antiviral responses upon infection with SARS-CoV-2 variants remain elusive. Leveraging whole-cell proteomics, we determined host signaling pathways that are differentially modulated upon infection with the clinical isolates of the ancestral SARS-CoV-2 B.1 and the variants of concern Delta and Omicron BA.1. Our findings illustrate alterations in the global host proteome landscape upon infection with SARS-CoV-2 variants and the resulting host immune responses. Additionally, viral proteome kinetics reveal declining levels of viral protein expression during Omicron BA.1 infection when compared to ancestral B.1 and Delta variants, consistent with its reduced replication rates. Moreover, molecular assays reveal deferral activation of specific host antiviral signaling upon Omicron BA.1 and BA.2 infections. Our study provides an overview of host proteome profile of multiple SARS-CoV-2 variants and brings forth a better understanding of the instigation of key immune signaling pathways causative for the differential pathogenicity of SARS-CoV-2 variants. [Display omitted] •Omicron variants display attenuated replication kinetics in Calu-3 cells.•SARS-CoV-2 variants differently alter global host proteome landscapes.•Infection with SARS-CoV-2 variants elicits shared enrichment in host immune responses.•SARS-CoV-2 variants examined in this study induce IFN and NF-kB signaling.•Delayed host immune response activation upon infection with Omicron variants. SARS-CoV-2 has mutated over the past years to numerous variants of concern (VOCs). Employing quantitative whole-cell proteomics, we elucidate host cell immune responses upon infection with ancestral B.1, VOCs Delta, and Omicron BA.1 strains. Molecular assays further illustrate reduced viral protein levels and delayed host immune pathway response upon infection with Omicron BA.1 when compared to B.1 and Delta. Overall, this study offers insights into host proteome profiles and distinct immune kinetics of ancestral B.1, Delta, and Omicron BA.1 strains.