{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:35:35Z","timestamp":1785760535574,"version":"3.56.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Zika virus (ZIKV) is a neurotropic pathogen linked to neuropathogenesis in adults, causing conditions such as Guillain-Barr\u00e9 syndrome (GBS) and fatal encephalitis. Intracranial injection of virus in immunocompromised mice have shown neuroinflammation and subsequent brain damage. However, the mechanisms underlying ZIKV-induced neuroinflammation in immunocompetent adult mice via peripheral infection remain unclear. To investigate this, we utilized a murine model of ZIKV infection via footpad injection. Our findings reveal that acute ZIKV infection at 4 days post-infection (4 dpi) induces significant apoptosis and neuroinflammation in the adult brain, persisting up to 28 dpi. Notably, ZIKV infection triggers apoptosis in the hippocampus and cortex\u2014key regions involved in memory\u2014and induces early immune cell infiltration. Additionally, microglial activation occurs following infection at 7 dpi, with viral RNA detected in the brain. Bulk RNA sequencing of the hippocampus at 28 dpi further reveals the activation of inflammatory pathways, underscoring the prolonged neuroinflammatory response in the infected brain. Microglial activation is likely driven by infiltrating monocytes, as inhibiting monocyte recruitment reduced the expression of microglial activation genes. These results suggest that targeting monocyte-induced inflammatory mediators could be potential therapeutic interventions for ZIKV.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1597776","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:25:10Z","timestamp":1751606710000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Zika virus induces monocyte recruitment in the immunocompetent adult brain driving chronic inflammation"],"prefix":"10.3389","volume":"16","author":[{"given":"Josefina","family":"Garcia Diaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Jeung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou","family":"Legouez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Comlekoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yi","family":"Kuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young S.","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02340","article-title":"Complementary mechanisms potentially involved in the pathology of zika virus","volume":"9","author":"Ojha","year":"2018","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"571","DOI":"10.3390\/ph16040571","article-title":"Insights into Exosome Transport through the Blood\u2013Brain Barrier and the Potential Therapeutical Applications in Brain Diseases","volume":"16","author":"Abdelsalam","year":"2023","journal-title":"Pharmaceuticals"},{"key":"B3","doi-asserted-by":"publisher","first-page":"100491","DOI":"10.1016\/j.epidem.2021.100491","article-title":"Zika virus outbreak in Brazil under current and future climate","volume":"37","author":"Sadeghieh","year":"2021","journal-title":"Epidemics"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1602964","article-title":"Zika virus associated with meningoencephalitis","volume":"374","author":"Carteaux","year":"2016","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2016.08.297","article-title":"Fatal encephalitis associated with Zika virus infection in an adult","volume":"83","author":"Soares","year":"2016","journal-title":"J Clin Virol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00556-23","article-title":"Zika virus infection induces interleukin-1\u03b2-mediated inflammatory responses by macrophages in the brain of an adult mouse model","volume":"97","author":"Jeong","year":"2023","journal-title":"Goodrum F editor J Virol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.03.018","article-title":"Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid \u03b2 plaques","volume":"55","author":"Roy","year":"2022","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","first-page":"402","DOI":"10.2471\/BLT.17.201541","article-title":"Prevalence of asymptomatic Zika virus infection: a systematic review","volume":"96","author":"Haby","year":"2018","journal-title":"Bull World Health Organ"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.17648\/htbr-2021-125090","article-title":"Clinical manifestations and health outcomes associated with Zika virus infections in adults: A systematic review","volume":"15","author":"Halani","year":"2021","journal-title":"PloS Negl Trop Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2016.12.019","article-title":"Zika virus meningoencephalitis in an immunocompromised patient","volume":"92","author":"Schwartzmann","year":"2017","journal-title":"Mayo Clin Proc"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/1352458518781992","article-title":"Zika virus found in brain tissue of a multiple sclerosis patient undergoing an acute disseminated encephalomyelitis-like episode","volume":"25","author":"Alves-Leon","year":"2019","journal-title":"Mult Scler J"},{"key":"B12","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jcv.2016.10.024","article-title":"Zika virus epidemic in Brazil. I. Fatal disease in adults: Clinical and laboratorial aspects","volume":"85","author":"Azevedo","year":"2016","journal-title":"J Clin Virol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.07.009","article-title":"Correlation between apoptosis and in situ immune response in fatal cases of microcephaly caused by zika virus","volume":"188","author":"De Sousa","year":"2018","journal-title":"Am J Pathol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"6518","DOI":"10.3390\/ijms24076518","article-title":"Inflammatory processes in alzheimer\u2019s disease\u2014Pathomechanism, diagnosis and treatment: A review","volume":"24","author":"Twarowski","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"240","DOI":"10.3390\/pathogens13030240","article-title":"Viral infections, are they a trigger and risk factor of alzheimer\u2019s disease","volume":"13","author":"Rippee-Brooks","year":"2024","journal-title":"Pathogens"},{"key":"B16","doi-asserted-by":"publisher","first-page":"65","DOI":"10.5607\/en22004","article-title":"Physiological roles of monomeric amyloid-\u03b2 and implications for alzheimer\u2019s disease therapeutics","volume":"31","author":"Jeong","year":"2022","journal-title":"Exp Neurobiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.neuron.2018.06.030","article-title":"Alzheimer\u2019s disease-associated \u03b2-amyloid is rapidly seeded by herpesviridae to protect against brain infection","volume":"99","author":"Eimer","year":"2018","journal-title":"Neuron"},{"key":"B18","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/s41420-022-00958-x","article-title":"Zika virus infection accelerates Alzheimer\u2019s disease phenotypes in brain organoids","volume":"8","author":"Lee","year":"2022","journal-title":"Cell Death Discov"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.997786","article-title":"Microglia morphophysiological diversity and its implications for the CNS","volume":"13","author":"Vidal-Itriago","year":"2022","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.125","article-title":"Microglia and macrophages in brain homeostasis and disease","volume":"18","author":"Li","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01024","article-title":"Wang G qing. Interaction of microglia and astrocytes in the neurovascular unit","volume":"11","author":"Liu","year":"2020","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.1003809","article-title":"The role of microglial exosomes in brain injury","volume":"16","author":"Chen","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.3390\/biomedicines10081800","article-title":"A\u03b2 and tau regulate microglia metabolism via exosomes in alzheimer\u2019s disease","volume":"10","author":"Zhao","year":"2022","journal-title":"Biomedicines"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.3390\/v16101612","article-title":"Monocyte and macrophage functions in oncogenic viral infections","volume":"16","author":"Echevarria-Lima","year":"2024","journal-title":"Viruses"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e99364","DOI":"10.1172\/jci.insight.99364","article-title":"Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment","volume":"3","author":"Andonegui","year":"2018","journal-title":"JCI Insight"},{"key":"B26","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s00401-021-02384-2","article-title":"Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function","volume":"143","author":"Spiteri","year":"2022","journal-title":"Acta Neuropathol (Berl)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"220491","DOI":"10.1098\/rsos.220491","article-title":"Estimating Zika virus attack rates and risk of Zika virus-associated neurological complications in Colombian capital cities with a Bayesian model","volume":"9","author":"Charniga","year":"2022","journal-title":"R Soc Open Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3390\/cells13020144","article-title":"Zika virus-infected monocyte exosomes mediate cell-to-cell viral transmission","volume":"13","author":"Mart\u00ednez-Rojas","year":"2024","journal-title":"Cells"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3890","DOI":"10.1038\/s41467-019-11866-7","article-title":"Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice","volume":"10","author":"Figueiredo","year":"2019","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","first-page":"9451","DOI":"10.3390\/ijms25179451","article-title":"Sustained microglial activation promotes synaptic loss and neuronal dysfunction after recovery from ZIKV infection","volume":"25","author":"Kim","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2300466","DOI":"10.1080\/22221751.2023.2300466","article-title":"Immunocompetent mouse models revealed that S100A4 + monocytes\/macrophages facilitate long-term Zika virus infection in the testes","volume":"13","author":"Yang","year":"2024","journal-title":"Emerg Microbes Infect"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.3390\/v13112244","article-title":"From mosquito bites to sexual transmission: evaluating mouse models of zika virus infection","volume":"13","author":"Balint","year":"2021","journal-title":"Viruses"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.773191","article-title":"Zika virus neuropathogenesis: the different brain cells, host factors and mechanisms involved","volume":"13","author":"Komarasamy","year":"2022","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.007555","article-title":"IL-1\u03b2\/TNF-\u03b1\/IL-6 inflammatory cytokines promote STAT1-dependent induction of CH25H in Zika virus\u2013infected human macrophages","volume":"294","author":"Magoro","year":"2019","journal-title":"J Biol Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01528-8","article-title":"SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity","volume":"24","author":"Fixsen","year":"2023","journal-title":"Nat Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20232000","article-title":"Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy","volume":"221","author":"Toral-Rios","year":"2024","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2008.00195.x","article-title":"Brain extracellular matrix in neurodegeneration","volume":"19","author":"Bonneh-Barkay","year":"2009","journal-title":"Brain Pathol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/9396021","article-title":"The roles of monocyte and monocyte-derived macrophages in common brain disorders","volume":"2020","author":"Zhao","year":"2020","journal-title":"BioMed Res Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb2119","article-title":"Fate mapping via CCR2-CreER mice reveals monocyte-to-microglia transition in development and neonatal stroke","volume":"6","author":"Chen","year":"2020","journal-title":"Sci Adv"},{"key":"B40","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41467-017-02645-3","article-title":"Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1\u03b2 secretion","volume":"9","author":"Wang","year":"2018","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2014.120","article-title":"Role of CCR2 in inflammatory conditions of the central nervous system","volume":"34","author":"Chu","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4110\/in.2018.18.e5","article-title":"Tissue-specific role of CX3CR1 expressing immune cells and their relationships with human disease","volume":"18","author":"Lee","year":"2018","journal-title":"Immune Netw"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02780","article-title":"Heterozygous CX3CR1 deficiency in microglia restores neuronal \u03b2-amyloid clearance pathways and slows progression of alzheimer\u2019s like-disease in PS1-APP mice","volume":"10","author":"Hickman","year":"2019","journal-title":"Front Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/s41419-019-1425-4","article-title":"P2Y12 regulates microglia activation and excitatory synaptic transmission in spinal lamina II neurons during neuropathic pain in rodents","volume":"10","author":"Yu","year":"2019","journal-title":"Cell Death Dis"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3190","DOI":"10.3390\/jcm12093190","article-title":"Long-term effects of SARS-coV-2 in the brain: clinical consequences and molecular mechanisms","volume":"12","author":"Granholm","year":"2023","journal-title":"J Clin Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12974-019-1596-z","article-title":"Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection","volume":"16","author":"Pokorna Formanova","year":"2019","journal-title":"J Neuroinflammation"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.10.049","article-title":"The hippocampus","volume":"25","author":"Knierim","year":"2015","journal-title":"Curr Biol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ncl.2021.08.006","article-title":"Infectious meningitis and encephalitis","volume":"40","author":"Bystritsky","year":"2022","journal-title":"Neurol Clin"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0200-8","article-title":"Lipidome alterations in human prefrontal cortex during development, aging, and cognitive disorders","volume":"25","author":"Yu","year":"2020","journal-title":"Mol Psychiatry"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1604263113","article-title":"Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus","volume":"113","author":"Varvel","year":"2016","journal-title":"Proc Natl Acad Sci"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2647","DOI":"10.3390\/cells10102647","article-title":"Roles of crosstalk between astrocytes and microglia in triggering neuroinflammation and brain edema formation in 1,2-dichloroethane-intoxicated mice","volume":"10","author":"Yang","year":"2021","journal-title":"Cells"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1597776\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:25:13Z","timestamp":1751606713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1597776\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2025.1597776"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1597776","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]},"article-number":"1597776"}}