Cox, A.; Nguyen, W.; Tang, B.; Yan, K.; Potadar, A.; Ziegman, R.; Hartel, G.; Nguyen, Q.; Hodson, M.; Suhrbier, A.; Bishop, C. R.; Rawle, D.

Japanese encephalitis virus (JEV) remains the leading cause of viral encephalitis across the Asia-Pacific region, with approximately 70,000 symptomatic infections each year and fewer than one third of patients making a full neurological recovery. While successful control of JEV requires immune responses that can clear infection without driving damaging neuroinflammation, the mechanisms that mediate the shift from viral clearance to restoration of homeostasis remain unknown. Here we identify apolipoproteinE (ApoE) as a key regulator of the inflammation resolution processes that underpin recovery from Japanese encephalitis. Using a mouse model that captures asymptomatic, symptomatic and lethal disease trajectories, together with single-cell spatial transcriptomics and bulk RNA-seq, we show that Apoe expression is strongly upregulated in microglia, myeloid cells, and T cells of symptomatic survivors, which adopt an anti-inflammatory phenotype during recovery. In contrast, immune cells in mice with lethal disease fail to induce Apoe and remain locked in a pro-inflammatory state. Apoe upregulation occurs early during resolution and aligns with transcriptional programs associated with enhanced phagocytosis, antigen cross-presentation, anti-inflammatory polarisation and suppression of cholesterol biosynthesis. Consistent with these findings, ApoE-deficient mice infected with JEV mount dysregulated immune responses, deteriorate more rapidly, and are unable to recover once symptomatic. To explore the relevance of these findings in humans, we analysed APOE protein isoforms in cerebrospinal fluid (CSF) from hospitalised acute encephalitis syndrome (AES) patients in central Laos. APOE occurs in three main isoforms (E2, E3, E4), each with distinct neurobiological properties. APOE2-carriers had significantly lower CSF neutrophil percentages and a significantly reduced hospital admission duration, consistent with its recognised neuroprotective characteristics, including stronger anti-inflammatory signalling, better maintenance of glial homeostasis, and improved neuronal survival. Taken together, these findings identify ApoE as a key molecular switch that resolves neuroinflammation and restores brain homeostasis after JEV infection, with APOE2 associated with more rapid recovery from AES, highlighting ApoE-dependent and isoform-specific resolution pathways as promising therapeutic targets for pathological encephalitis.