Genetically Divergent Human Cytomegalovirus and SARS-CoV-2 Differentially Reprogram Host Phospholipid Metabolism

Abstract

Virus infection reprograms host lipid metabolism. Identifying which host pathways are reprogrammed in infection improves our understanding of virus biology and can provide novel therapeutic targets for antiviral development. In these studies, we use high-resolution mass spectrometry to identify which class-specific lipid changes are induced by two genetically divergent DNA and RNA viruses. Further, we investigate which host pathways HCMV reprograms to promote lipid levels. Finally, we test how shRNA KD of metabolic enzymes and nutrient starvation impacts lipid levels to determine which host pathways are essential for virus replication.Here, we demonstrate that genetically divergent HCMV and SARS-CoV-2 differentially reprogram host phospholipid metabolism to promote the levels of two different classes of phospholipids. Moreover, we identify which host synthesis pathways HCMV infection reprograms, and the impact nutrient starvation has on virus replication. From our lipidomic studies we determine that HCMV infection promotes host phospholipid synthesis via the de novo PC pathway. Furthermore, the lack of observable PEMT and LPCAT metabolic activity when choline is withdrawn suggest cells may respond using a compensatory host response which HCMV takes advantage of to replicate under choline-starved conditions.