SARS-CoV-2 infection disrupts CNS energy metabolism and immune homeostasis in African green monkeys

Abstract Persistent neurological symptoms are frequently reported following SARS-CoV-2 infection, yet the underlying neuropathology of post-acute sequelae of COVID-19 (PASC) remains unclear. Here, we characterize long-term brain changes in African green monkeys (AGMs) at 18 weeks post-infection (wpi). While neuronal apoptosis and microhemorrhages largely resolved by 18 wpi, chronic neuroinflammation persisted, with pronounced microglial and astrocyte activation and increased microglial nodule formation in the brainstem and cerebellum. Hypoxia-inducible factor-1 α (HIF-1 α) remained elevated in brain endothelial cells despite normoxia, implicating non-hypoxic stabilizing mechanisms. Cerebrospinal fluid metabolomics revealed altered branched-chain amino acids, cortisol, adenosine, and tricarboxylic acid cycle metabolites, consistent with sustained immunometabolic reprogramming. Behaviorally, infected AGMs showed reduced cognitive engagement and gustatory deficits. These data suggest that SARS-CoV-2 induces long-lasting neuroimmune and metabolic disturbances that may underlie persistent symptoms and contribute to premature neurodegeneration.