Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling
5 affiliations
- 1Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont, United States of America.
- 2Vermont Complex Systems Institute, University of Vermont, Burlington, Vermont, United States of America.
- 3Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
- 4Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
- 5Department of Physiology and Biophysics, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, United States of America.
Abstract
Herpes simplex virus type 1 (HSV-1) is a neurotropic pathogen capable of invading the central nervous system (CNS) and is associated with chronic neuroinflammation, cognitive impairment, and neurodegenerative disease. While microglia orchestrate the initial immune response to HSV‑1, the molecular mechanisms that regulate their sustained neuroinflammatory activity in vivo remain poorly understood. To define the transcriptional and epigenetic mechanisms that shape microglial responses during acute HSV-1 infection in vivo, we have, for the first time, integrated single‑nucleus RNA sequencing, chromatin accessibility profiling, and spatial proteomics and transcriptomics in an intranasal HSV‑1 infection model. Single-cell multiome analysis of CD11b⁺ nuclei identified transcriptionally and epigenetically distinct microglial and macrophage populations. HSV-1 infection redistributed monocyte-lineage states, with a marked overrepresentation of interferon (IFN)‑responsive microglia and macrophage-associated populations characterized by amplification of Stat1/2, Irf1, and Cebpb rather than reflecting uniform inflammatory activation. In parallel, homeostatic microglial gene signatures (e.g., ApoE, Cst3) were reduced following HSV-1 infection. Spatial transcriptomics localized HSV‑1 antigen to discrete brainstem regions, which were enriched for predicted STAT1/2, IRF1, and CEBPB‑regulated targets identified through single‑nuclei analysis, demonstrating that these inferred transcriptional networks are activated within anatomically defined regions in vivo. Complementary spatial proteomics further confirmed increased microglial activation and astrocytic responses specifically within HSV-1 antigen-positive regions. Together, these integrated multiomic analyses demonstrate that HSV-1 induces localized transcriptional and epigenetic remodeling of microglia dominated by IFN-driven regulatory programs and a loss of homeostatic signatures. By linking single-cell regulatory architecture to spatially restricted tissue responses, our findings provide mechanistic insight into how localized viral infection sustains neuroinflammation, contributing to long-term neurological vulnerability and neurodegenerative disease risk. Author summary: Herpes simplex virus type 1 (HSV-1) infects nearly 60% of the population and establishes latency within the nervous system. Growing evidence links HSV-1 infection and reactivation to Alzheimer’s disease (AD) pathology. However, the contribution of HSV-1 to neurodegenerative disease risk remains poorly understood.
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BibTeX
@article{frietze2026intranasal,
title = {{Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling}},
author = {Seth Frietze and Cameron Lunn and Dean Oldham and Joseph R Boyd and Andrew N Bubak and Amalia Bustillos Saucedo and Maria A Nagel and Diego Restrepo and Kimberley D Bruce and Christy S Niemeyer},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014684},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014684},
note = {CC BY},
}
RIS
TY - JOUR
TI - Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling
AU - Seth Frietze
AU - Cameron Lunn
AU - Dean Oldham
AU - Joseph R Boyd
AU - Andrew N Bubak
AU - Amalia Bustillos Saucedo
AU - Maria A Nagel
AU - Diego Restrepo
AU - Kimberley D Bruce
AU - Christy S Niemeyer
PY - 2026
DA - 2026/10/14
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014684
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014684
AB - Herpes simplex virus type 1 (HSV-1) is a neurotropic pathogen capable of invading the central nervous system (CNS) and is associated with chronic neuroinflammation, cognitive impairment, and neurodegenerative disease. While microglia orchestrate the initial immune response to HSV‑1, the molecular mechanisms that regulate their sustained neuroinflammatory activity in vivo remain poorly understood. To define the transcriptional and epigenetic mechanisms that shape microglial responses during acute HSV-1 infection in vivo, we have, for the first time, integrated single‑nucleus RNA sequencing, chromatin accessibility profiling, and spatial proteomics and transcriptomics in an intranasal HSV‑1 infection model. Single-cell multiome analysis of CD11b⁺ nuclei identified transcriptionally and epigenetically distinct microglial and macrophage populations. HSV-1 infection redistributed monocyte-lineage states, with a marked overrepresentation of interferon (IFN)‑responsive microglia and macrophage-associated populations characterized by amplification of Stat1/2, Irf1, and Cebpb rather than reflecting uniform inflammatory activation. In parallel, homeostatic microglial gene signatures (e.g., ApoE, Cst3) were reduced following HSV-1 infection. Spatial transcriptomics localized HSV‑1 antigen to discrete brainstem regions, which were enriched for predicted STAT1/2, IRF1, and CEBPB‑regulated targets identified through single‑nuclei analysis, demonstrating that these inferred transcriptional networks are activated within anatomically defined regions in vivo. Complementary spatial proteomics further confirmed increased microglial activation and astrocytic responses specifically within HSV-1 antigen-positive regions. Together, these integrated multiomic analyses demonstrate that HSV-1 induces localized transcriptional and epigenetic remodeling of microglia dominated by IFN-driven regulatory programs and a loss of homeostatic signatures. By linking single-cell regulatory architecture to spatially restricted tissue responses, our findings provide mechanistic insight into how localized viral infection sustains neuroinflammation, contributing to long-term neurological vulnerability and neurodegenerative disease risk. Author summary: Herpes simplex virus type 1 (HSV-1) infects nearly 60% of the population and establishes latency within the nervous system. Growing evidence links HSV-1 infection and reactivation to Alzheimer’s disease (AD) pathology. However, the contribution of HSV-1 to neurodegenerative disease risk remains poorly understood.
SN - 1553-7374
SN - 1553-7366
ER -