{ "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.", "abstract_shown": true, "affiliations": [ "Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont, United States of America.", "Vermont Complex Systems Institute, University of Vermont, Burlington, Vermont, United States of America.", "Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.", "Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.", "Department of Physiology and Biophysics, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, United States of America." ], "article_type": "Research Article", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0 ], "name": "Seth Frietze" }, { "affs": [ 0, 1 ], "name": "Cameron Lunn" }, { "affs": [ 2 ], "name": "Dean Oldham" }, { "affs": [ 0 ], "name": "Joseph R Boyd" }, { "affs": [ 3 ], "name": "Andrew N Bubak" }, { "affs": [ 3 ], "name": "Amalia Bustillos Saucedo" }, { "affs": [ 3 ], "name": "Maria A Nagel" }, { "affs": [ 4 ], "name": "Diego Restrepo" }, { "affs": [ 2 ], "name": "Kimberley D Bruce" }, { "affs": [ 3 ], "name": "Christy S Niemeyer", "orcid": "0000-0001-6830-6522" } ], "bibtex": "https://research.draconitic.com/paper/1892zgtcdn45p.bib", "cited_by": 1, "doi": "10.1371/journal.ppat.1014684", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014684", "id": "1892zgtcdn45p", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014684", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2808|Neuroinflammation and Neurodegeneration Mechanisms" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/DNA-binding proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Regulatory proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Glial cells/Microglial cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Chromosome biology/Chromatin" ], [ "plos", "/Biology and life sciences/Computational biology/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Genetics/Epigenetics/Chromatin" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Chromatin" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Regulons" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Transcription factors" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Transcriptional control" ], [ "plos", "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Physiology/Physiological processes/Homeostasis" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ] ], "openalex": "W7221804443", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014684&type=printable", "pmcid": "PMC13693987", "pmid": "42873820", "published": "2026-10-14", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/1892zgtcdn45p.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.ppat.1014684", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014684" }, { "first_seen": "2026-10-30T12:18:46Z", "native_id": "MED:42873820", "source": "europepmc", "url": "https://europepmc.org/article/MED/42873820" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:gene expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:genetics", "subfield": "genetics-genomics" } ], "title": "Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling", "title_text": "Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:46Z", "url": "https://research.draconitic.com/paper/1892zgtcdn45p", "venue": "PLOS Pathogens", "versions": [] }