Virus-specific host responses and gene signatures following infection with major SARS-CoV-2 variants of concern: role of ZBP1 in viral clearance and lung inflammation

• DOI: 10.3389/fimmu.2025.1557535
• Publication Date: 2025-05-09T05:34:42Z
• Authors: Amany Elsharkawy; Hamid Reza Jahantigh; Anchala Guglani; Shannon Stone; Komal Arora; Mukesh Kumar
• Keywords: Pathogenesis

SARS-CoV-2 can cause severe lung damage due to uncontrolled viral replication or/and excessive inflammation. New variants of concern (VOCs) have raised additional concerns disparate pathogenicity and possible enhanced virulence. Herein, using RNA sequencing, we performed a comparative transcriptomic analysis following infection with major VOCs. We evaluated the transcriptional changes induced in lungs K18-hACE2 mice ancestral B.1 lineage (Wuhan), B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.1.529 (Omicron) or mouse-adapted (MA10). Our work reveals molecular basis pathological hallmarks associated infection. report that B.1, pre-Omicron VOCs, MA10 induce similar fingerprints inflammation immune activation mice. Analysis differentially expressed genes revealed both shared variant-specific responses, key markers such as Cxcl10, Zbp1, Ifit3, Isg15, Rsad2, Irf7 consistently upregulated across variants. Clustering highly variable samples two variant groups distinguished by upregulation antigen presentation immune-related ( e.g. Retnla, Saa3, Plac8, Ly6c2, H2-D1, H2-K1 ). Delta, Beta, Alpha, showed elevated expression, whereas Wuhan Omicron exhibited attenuated responses. In addition, show Z-DNA-binding protein 1 (ZBP1) plays role clearance after ZBP1 deficiency resulted reduced expression cell death-associated virus-induced death Furthermore, knockout an inflammatory response production proinflammatory cytokines chemokines decreased macrophage infiltration lungs. These results suggest enhancing during Altogether, our study provides insights into pathogenesis mice, facilitating identification biomarkers development potential therapeutic targets.