Lipid Metabolism in SARS-CoV-2 Infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-opts host lipid metabolic pathways at multiple stages of its life cycle, from initial membrane fusion to virion assembly and egress. The viral envelope, derived from host membranes, is rich in cholesterol and phospholipids, which contribute to membrane fluidity and curvature during entry and budding. Host lipid regulators, notably sterol regulatory element-binding proteins (SREBPs), are upregulated upon infection, driving fatty acid synthesis and promoting biogenesis of lipid droplets. These dynamic organelles serve as platforms for viral replication complexes, supplying essential lipids and energy reserves. Concurrent remodelling of glycerophospholipid and sphingolipid profiles supports membrane rearrangements required for double-membrane vesicle formation. Disruption of cholesterol trafficking via Niemann-Pick C1 impairs viral fusion, while alterations in lipoprotein receptors facilitate entry of lipoviral particles. Dysregulation of systemic lipid homeostasis is evidenced in post-infection cohorts, with elevated triglycerides and reduced high-density lipoprotein cholesterol levels linked to prolonged inflammatory states. This intimate interplay between SARS-CoV-2 and lipid metabolism has inspired therapeutic strategies targeting key enzymes, transporters and lipid-signalling pathways to curb viral replication and mitigate metabolic sequelae.

Research from Nature Portfolio

Recent studies have uncovered Niemann-Pick C1 (NPC1) as a critical co-factor in the late endosomal entry of SARS-CoV-2. Small-molecule inhibitors targeting NPC1 binding to the spike protein effectively block membrane fusion and prevent infection by multiple coronavirus variants, highlighting endosomal cholesterol transport as a viable antiviral target. Parallel investigations have illuminated the role of SREBP-driven lipid synthesis in coronavirus replication. Pharmacological modulation of SREBP cleavage reduces de novo lipogenesis and disrupts the formation of double-membrane replication organelles, curbing viral RNA synthesis across diverse human coronaviruses and suggesting a broad-spectrum antiviral approach centred on lipogenic transactivation pathways.

Lipid Metabolism in SARS-CoV-2 Infection publication trend

The graph below shows the total number of articles in lipid metabolism in sars-cov-2 infection across all publications each year (not limited to Nature Index journals).

Technical terms

Lipid droplets: Intracellular organelles composed of a neutral lipid core surrounded by a phospholipid monolayer that serve as lipid storage and sites for viral replication complex assembly.

SREBP (Sterol regulatory element-binding protein): A family of transcription factors that regulate expression of genes involved in cholesterol and fatty acid synthesis.

Niemann-Pick C1 (NPC1): A lysosomal membrane protein responsible for cholesterol egress; acts as a co-factor for viral fusion in late endosomes.

Lipoviral particles: Virus particles that incorporate host-derived lipids and apolipoproteins, facilitating receptor-mediated entry into target cells.

Dyslipidemia: An abnormal lipid profile in the blood, typically characterised by elevated triglycerides, low high-density lipoprotein cholesterol and altered cholesterol ratios.

References

1. Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1. Nature Communications (2024).
2. A six-year study in a real-world population reveals an increased incidence of dyslipidemia during COVID-19. Journal of Clinical Investigation (2024).
3. The Apolipoprotein E neutralizing antibody inhibits SARS‐CoV‐2 infection by blocking cellular entry of lipoviral particles. MedComm (2023).
4. Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication. Viruses (2019).
5. SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target. Nature Communications (2019).
6. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLOS Pathogens (2020).