Intranasal HSV-1 Infection Drives Region-Specific Interferon-Dominant Microglial Remodeling

Area of Science:

• Neuroimmunology
• Virology
• Genomics

Background:

• Herpes simplex virus type 1 (HSV-1) is a neurotropic virus impacting the central nervous system (CNS).
• HSV-1 is linked to chronic neuroinflammation, cognitive decline, and neurodegenerative diseases.
• Microglial roles in sustained HSV-1 neuroinflammation are not fully understood.

Purpose of the Study:

• To define transcriptional and epigenetic mechanisms of microglial responses during HSV-1 infection.
• To investigate how HSV-1 shapes microglial activity in vivo.
• To understand the molecular basis of HSV-1-induced neuroinflammation.

Main Methods:

• Integrated single-nucleus RNA sequencing, chromatin accessibility, and spatial transcriptomics.
• Utilized a physiologically relevant intranasal HSV-1 infection model.
• Analyzed CD11b+ nuclei to identify distinct microglial and macrophage populations.

Main Results:

• HSV-1 infection induced distinct interferon (IFN)-responsive microglial and macrophage populations.
• Identified amplification of STAT1/2, IRF1, and CEBPB regulons in IFN-responsive states.
• Observed reduced homeostatic microglial gene signatures (e.g., ApoE, Cst3) and localized HSV-1 to brainstem regions.

Conclusions:

• HSV-1 drives significant transcriptional and epigenetic remodeling of microglia.
• Characterized by IFN-responsive states and loss of homeostatic signatures.
• Provides mechanistic insight into persistent neuroinflammation and neurological disease risk.