{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:42:46Z","timestamp":1792618966216,"version":"4.5.0"},"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National institute for health","award":["K12TR004412"],"award-info":[{"award-number":["K12TR004412"]}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG079217"],"award-info":[{"award-number":["R01 AG079217"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R21AG091650"],"award-info":[{"award-number":["R21AG091650"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG079193"],"award-info":[{"award-number":["R01 AG079193"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R21AG093719"],"award-info":[{"award-number":["R21AG093719"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\u20111, the molecular mechanisms that regulate their sustained neuroinflammatory activity\n                    <jats:italic>in vivo<\/jats:italic>\n                    remain poorly understood. To define the transcriptional and epigenetic mechanisms that shape microglial responses during acute HSV-1 infection\n                    <jats:italic>in vivo,<\/jats:italic>\n                    we have, for the first time, integrated single\u2011nucleus RNA sequencing, chromatin accessibility profiling, and spatial proteomics and transcriptomics in an intranasal HSV\u20111 infection model. Single-cell multiome analysis of CD11b\u207a nuclei identified transcriptionally and epigenetically distinct microglial and macrophage populations. HSV-1 infection redistributed monocyte-lineage states, with a marked overrepresentation of interferon (IFN)\u2011responsive microglia and macrophage-associated populations characterized by amplification of\n                    <jats:italic>Stat1\/2, Irf1, and Cebpb<\/jats:italic>\n                    rather than reflecting uniform inflammatory activation. In parallel, homeostatic microglial gene signatures (\n                    <jats:italic>e.g., ApoE, Cst3<\/jats:italic>\n                    ) were reduced following HSV-1 infection. Spatial transcriptomics localized HSV\u20111 antigen to discrete brainstem regions, which were enriched for predicted STAT1\/2, IRF1, and CEBPB\u2011regulated targets identified through single\u2011nuclei analysis, demonstrating that these inferred transcriptional networks are activated within anatomically defined regions\n                    <jats:italic>in vivo<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014684","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:46:30Z","timestamp":1791999990000},"page":"e1014684","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intranasal HSV\u20111 infection drives region\u2011specific interferon\u2011dominant microglial remodeling"],"prefix":"10.1371","volume":"22","author":[{"given":"Seth","family":"Frietze","sequence":"first","affiliation":[{"name":"University of Vermont","place":["Burlington, Vermont, United States of America"],"department":["Department of Medical Laboratory Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Lunn","sequence":"additional","affiliation":[{"name":"University of Vermont","place":["Burlington, Vermont, United States of America"],"department":["Department of Medical Laboratory Sciences"]},{"name":"University of Vermont","place":["Burlington, Vermont, United States of America"],"department":["Vermont Complex Systems Institute"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Oldham","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Boyd","sequence":"additional","affiliation":[{"name":"University of Vermont","place":["Burlington, Vermont, United States of America"],"department":["Department of Medical Laboratory Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Bubak","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Department of Neurology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia Bustillos","family":"Saucedo","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Department of Neurology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Nagel","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Department of Neurology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Restrepo","sequence":"additional","affiliation":[{"name":"Stony Brook University","place":["Stony Brook, New York, United States of America"],"department":["Department of Physiology and Biophysics, Renaissance School of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley D.","family":"Bruce","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6830-6522","authenticated-orcid":true,"given":"Christy S.","family":"Niemeyer","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Department of Neurology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"issue":"11","key":"ppat.1014684.ref001","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00968-24","article-title":"Olfactory and trigeminal routes of HSV-1 CNS infection with regional microglial heterogeneity","volume":"98","author":"CS Niemeyer","year":"2024","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014684.ref002","doi-asserted-by":"crossref","DOI":"10.1111\/bpa.13116","article-title":"A\u03b2 plaques do not protect against HSV-1 infection in a mouse model of familial Alzheimer\u2019s disease, and HSV-1 does not induce A\u03b2 pathology in a model of late onset Alzheimer\u2019s disease","volume":"33","author":"OV Bocharova","year":"2023","journal-title":"Brain 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