Divergent lipid utilization strategies of SARS-CoV-2 and MERS-CoV revealed by comparative multi-omics profiling of infected mouse lung tissues

Background Coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome (MERS-CoV), cause respiratory infections with distinct clinical outcomes and case fatality rates. However, the molecular basis of these differences remains unclear. In this study, we sought to define virus-specific host metabolic programs by directly comparing multiomics profiles of the lungs of lethally infected mouse models. Methods We performed integrated multiomics analyses, including untargeted metabolomics, transcriptomics, and targeted lipidomics, of lung tissues from human angiotensin-converting enzyme 2 (hiACE2)-human dipeptidyl peptidase 4 (hDPP4) double-knock-in (DKI) mice infected in SARS-CoV-2 or MERS-CoV. Data Integration Analysis and Biomarker discovery using Latent cOmponents (DIABLO) was applied across all three omics layers to identify key distinguishing molecular patterns. Additionally, in vitro lipid droplet kinetics were examined in infected Vero E6 cells to validate temporal differences in lipid remodeling. Results We identified two distinct strategies for lipid utilization. SARS-CoV-2 infection showed strong activation of energy and amino acid metabolism at an early stage of infection (3 days post infection, DPI), whereas MERS-CoV infection was characterized by sustained alterations in lipid and nucleotide metabolism. Integrative DIABLO analysis of all three omics layers revealed that the key distinguishing features clustered into virus-specific molecular signatures: a triacylglycerol–lipid droplet–interferon axis for SARS-CoV-2 and a phospholipid–sphingolipid–membrane hub for MERS-CoV. In vitro lipid droplet kinetics in infected Vero E6 cells confirmed this temporal difference, with SARS-CoV-2 peaking earlier than MERS-CoV. Conclusion These findings show that β-CoVs exploit host lipid metabolism through virus-specific and time-dependent remodeling programs, providing a framework for understanding differential pathogenesis and developing host-directed antiviral strategies.