Immunological and molecular drivers of severe cases in the SARS-CoV-2 Delta wave revealed through genomic analysis of a COVID-19 cohort 2863

Abstract Description SARS-CoV-2, the virus behind the COVID-19 pandemic, has continuously evolved, giving rise to variants of concern (VOCs) with distinct traits. For example, the Delta variant caused severe disease, while Omicron caused milder illness but was more transmissible. Although the pandemic has subsided, SARS-CoV-2 persists in human and animal populations, raising the likelihood of new VOCs emerging from evolutionary mutations. Understanding how genetic changes affect virulence, transmission, and tropism is critical for future preparedness. We analyzed over 12,000 SARS-CoV-2-positive samples from Karnataka during the COVID-19 pandemic, sequencing 850 using Illumina technology to investigate viral evolution. These samples spanned the Wuhan, Delta, and Omicron waves. Analysis revealed a positive link between disease severity and viral load, a negative correlation with vaccination, and no gender-based differences. Mutational hotspot mapping identified critical changes in the Spike, nucleoprotein, ORF7, ORF8, NSP13, and NSP14 regions associated with severe COVID-19 disease. Specifically, mutations in the ORF8 protein of Delta VOC were associated with increased secretion of the protein, leading to enhanced inflammatory signaling through the NFkB pathway. Furthermore, specific mutations in the ORF7 protein of Delta VOC were associated with the modulation of Autophagy to promote viral replication. Further experiments to validate these findings through Viral reverse genetics are ongoing. Funding Sources Crypto-relief, DBT-Wellcome trust Indian Alliance Topic Categories Immune Mechanisms of Human Disease (HUM)