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RATIONALE Brain injury induces systemic immunosuppression increasing the risk of viral reactivations and altering neurological recovery. OBJECTIVES To determine if systemic immune alterations and lung replication of Herpesviridae are associated and can help predict outcomes after brain injury. METHODS We collected peripheral blood mononuclear cells in severely brain-injured patients requiring invasive mechanical ventilation. We systematically searched for respiratory Herpes Simplex Virus (HSV) replications in tracheal aspirates. We also performed CHiP-sequencing, RNA-sequencing and in vitro functional assays of monocytes and CD4 T cells collected on day 1 to characterize immune response to severe acute brain injury. The primary outcome was the Glasgow outcome scale Extended (GOS-E) at 6 months. MEASUREMENTS AND MAIN RESULTS In 344 severe brain-injured patients, lung HSV reactivations were observed in 39% of patients seropositive for HSV, and independently associated with poor neurological recovery at six months (hazard ratio 1.90, 95%CI 1.08-3.57). WGNA analyses of the transcriptomic response of monocytes to brain injury defined a module of 721 genes, including PD-L1 and CD80, enriched for the binding DNA motif of the transcriptional factor Zeb2, and whose ontogenic analyses revealed decreased interferon--mediated and anti-viral response signaling pathways. This monocyte signature was preserved in a validation cohort and predicted the neurological outcome at 6 months with good accuracy (AUC 0.786, 95%CI 0.593-0.978). CONCLUSIONS A specific monocyte signature is associated with HSV reactivation and predicts recovery after brain injury. The alterations of the immune control of Herpesviridae replication are understudied and represent a novel therapeutic target.