Subclinical Neonatal HSV-1 Infection Triggers Immune Responses and Modulates Neurological Pathways Leading to Long-Term Sequelae

Here, we show that neonatal exposure to herpes simplex virus type 1 (HSV-1), even in the absence of overt symptoms, induces persistent transcriptional and cellular changes in the brain that correlate with anxiety-like behavior later in life. Neonatal mice were subclinically infected intranasally with HSV-1 and assessed at acute (3 days post-infection) and chronic (5–6 weeks post-infection) stages using cytokine profiling, bulk RNA sequencing, and spatial transcriptomics.

We observed sustained elevation of immune mediators, including CXCL10, IL-6, and IL-10, at both acute and chronic stages. Bulk RNA-seq analysis identified over 490 differentially expressed genes, with distinct expression modules that diverged significantly between early and late infection phases. Notably, several modules exhibited minimal acute changes but showed pronounced dysregulation chronically, highlighting a temporal evolution in gene expression extending beyond the initial immune response.