Brain corticogenesis promotes SARS-CoV-2 neuro-glial tropism through lipid-dependent viral replication

ABSTRACT: While extensive research has examined the neuroinvasiveness of SARS-CoV-2, its relationship with brain maturation remains unclear. Using a multi-omics approach, we established cerebral organoids (CBOs) at day 60 (EB60) and day 120 (EB120) to model immature and mature developmental stages. We found that enhanced corticogenesis and gliogenesis during maturation are associated with substantial alterations in lipid metabolism, functionally linking these processes to coordinated molecular and functional brain development. To directly characterize the lipid landscape accompanying brain maturation, we performed untargeted lipidomics on healthy EB60 and EB120 organoids, revealing a broad remodeling of the lipid metabolome in mature CBOs and providing a quantitative basis for the observed metabolic shift. Leveraging this model, we provide the first quantitative insights into long-term viral propagation kinetics up to 20 days post-infection, revealing significantly higher infectivity in mature CBOs. Single-cell transcriptomics, RT-qPCR and immunohistochemistry revealed upregulation of lipid-associated genes in EB120, suggesting a key driver of increased susceptibility. Consistently, pharmacological lipid reduction attenuated SARS-CoV-2 infection. Our findings establish a mechanistic link between intrinsic brain maturation and viral susceptibility mediated by lipid remodeling, supported by lipidomic profiling of healthy organoids, and suggest lipid-lowering strategies as potential candidates for therapeutic repurposing in COVID-19.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14790 | MetaboLights | 2026-06-18

REPOSITORIES: MetaboLights