{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:38:07Z","timestamp":1792132687807,"version":"4.4.0"},"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Viral infections of the central nervous system (CNS) are a major cause of morbidity largely due to lack of prevention and inadequate treatments. While mortality from viral CNS infections is significant, nearly two thirds of the patients survive. Thus, it is important to understand how the human CNS can successfully control virus infection and recover. Since it is not possible to study the human CNS throughout the course of viral infection at the cellular level, here we analyzed a non-lethal viral infection in the CNS of nonhuman primates (NHPs). We inoculated NHPs intracerebrally with a high dose of La Crosse virus (LACV), a bunyavirus that can infect neurons and cause encephalitis primarily in children, but with a very low (\u2264 1%) mortality rate. To profile the CNS response to LACV infection, we used an integrative approach that was based on comprehensive analyses of (i) spatiotemporal dynamics of virus replication, (ii) identification of types of infected neurons, (iii) spatiotemporal transcriptomics, and (iv) morphological and functional changes in CNS intrinsic and extrinsic cells. We identified the location, timing, and functional repertoire of optimal transcriptional and translational regulation of the primate CNS in response to virus infection of neurons. These CNS responses involved a well-coordinated spatiotemporal interplay between astrocytes, lymphocytes, microglia, and CNS-border macrophages. Our findings suggest a multifaceted program governing an optimal CNS response to virus infection with specific events coordinated in space and time. This allowed the CNS to successfully control the infection by rapidly clearing the virus from infected neurons, mitigate damage to neurophysiology, activate and terminate immune responses in a timely manner, resolve inflammation, restore homeostasis, and initiate tissue repair. An increased understanding of these processes may provide new therapeutic opportunities to improve outcomes of viral CNS diseases in humans.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012530","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T18:39:15Z","timestamp":1737571155000},"page":"e1012530","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatiotemporal profile of an optimal host response to virus infection in the primate central nervous system"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8906-9738","authenticated-orcid":true,"given":"Olga A.","family":"Maximova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Anzick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Sturdevant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence J.","family":"Faucette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"St. Claire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Whitehead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishore","family":"Kanakabandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong-mei","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Kash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery K.","family":"Taubenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Martens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey I.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"issue":"6","key":"ppat.1012530.ref001","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nri1105","article-title":"Immune responses to RNA-virus infections of the CNS","volume":"3","author":"DE Griffin","year":"2003","journal-title":"Nature reviews Immunology"},{"issue":"4","key":"ppat.1012530.ref002","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.chom.2013.03.010","article-title":"Virus infections in the nervous system","volume":"13","author":"OO Koyuncu","year":"2013","journal-title":"Cell host & microbe"},{"issue":"6","key":"ppat.1012530.ref003","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.immuni.2017.06.012","article-title":"Protective and Pathological Immunity during Central Nervous System Infections","volume":"46","author":"RS Klein","year":"2017","journal-title":"Immunity"},{"issue":"1","key":"ppat.1012530.ref004","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-virology-092917-043439","article-title":"Flaviviruses and the Central Nervous System: Revisiting Neuropathological Concepts.","volume":"5","author":"OA Maximova","year":"2018","journal-title":"Annual review of virology"},{"key":"ppat.1012530.ref005","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1146\/annurev-immunol-042718-041417","article-title":"Neuroinflammation During RNA Viral Infections","volume":"37","author":"RS Klein","year":"2019","journal-title":"Annual review of immunology"},{"issue":"2","key":"ppat.1012530.ref006","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1001\/jamaneurol.2014.3442","article-title":"Neuroinfectious diseases: a crisis in neurology and a call for action","volume":"72","author":"A. Nath","year":"2015","journal-title":"JAMA neurology"},{"issue":"3","key":"ppat.1012530.ref007","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/ana.20959","article-title":"West Nile virus neuroinvasive disease","volume":"60","author":"LE Davis","year":"2006","journal-title":"Annals of neurology"},{"issue":"8","key":"ppat.1012530.ref008","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1093\/jnen\/nlaa054","article-title":"Emergent Viral Infections of the CNS","volume":"79","author":"CA Wiley","year":"2020","journal-title":"Journal of neuropathology and experimental neurology"},{"issue":"1","key":"ppat.1012530.ref009","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0042-6822(03)00583-X","article-title":"Neurovirulence of yellow fever 17DD vaccine virus to rhesus monkeys","volume":"316","author":"RS Marchevsky","year":"2003","journal-title":"Virology"},{"issue":"22","key":"ppat.1012530.ref010","doi-asserted-by":"crossref","first-page":"12497","DOI":"10.1128\/JVI.78.22.12497-12507.2004","article-title":"ChimeriVax-West Nile virus live-attenuated vaccine: preclinical evaluation of safety, immunogenicity, and efficacy","volume":"78","author":"J Arroyo","year":"2004","journal-title":"Journal of virology"},{"issue":"1\u20132","key":"ppat.1012530.ref011","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF01314128","article-title":"Study on West Nile virus persistence in monkeys","volume":"75","author":"VV Pogodina","year":"1983","journal-title":"Archives of virology"},{"issue":"10","key":"ppat.1012530.ref012","first-page":"973","article-title":"Cellular inflammatory response to flaviviruses in the central nervous system of a primate host. The journal of histochemistry and cytochemistry: official journal of the","volume":"57","author":"OA Maximova","year":"2009","journal-title":"Histochemistry Society"},{"issue":"9","key":"ppat.1012530.ref013","doi-asserted-by":"crossref","first-page":"e0004980","DOI":"10.1371\/journal.pntd.0004980","article-title":"West Nile Virus Spreads Transsynaptically within the Pathways of Motor Control: Anatomical and Ultrastructural Mapping of Neuronal Virus Infection in the Primate Central Nervous System.","volume":"10","author":"OA Maximova","year":"2016","journal-title":"PLoS neglected tropical diseases."},{"key":"ppat.1012530.ref014","first-page":"10","article-title":"Virus infection of the CNS disrupts the immune-neural-synaptic axis via induction of pleiotropic gene regulation of host responses","author":"OA Maximova","year":"2021","journal-title":"Elife"},{"issue":"1","key":"ppat.1012530.ref015","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0891-5520(05)70410-4","article-title":"California-La Crosse encephalitis.","volume":"12","author":"JE McJunkin","year":"1998","journal-title":"Infectious disease clinics of North America."},{"issue":"3","key":"ppat.1012530.ref016","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1177\/19418744221077738","article-title":"An Overview of La Crosse Virus Disease.","volume":"12","author":"E Matthews","year":"2022","journal-title":"Neurohospitalist"},{"key":"ppat.1012530.ref017","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1743-422X-5-25","article-title":"La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys","volume":"5","author":"RS Bennett","year":"2008","journal-title":"Virology journal"},{"issue":"1","key":"ppat.1012530.ref018","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12974-017-0836-3","article-title":"Lymphocytes have a role in protection, but not in pathogenesis, during La Crosse Virus infection in mice","volume":"14","author":"CW Winkler","year":"2017","journal-title":"Journal of neuroinflammation"},{"issue":"2","key":"ppat.1012530.ref019","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00401-015-1433-0","article-title":"Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion","volume":"130","author":"CW Winkler","year":"2015","journal-title":"Acta neuropathologica"},{"issue":"1","key":"ppat.1012530.ref020","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1038\/s41467-023-37833-x","article-title":"Identification of age-specific gene regulators of La Crosse virus neuroinvasion and pathogenesis","volume":"14","author":"R Basu","year":"2023","journal-title":"Nature communications"},{"issue":"4","key":"ppat.1012530.ref021","first-page":"447","article-title":"Mechanisms of bunyavirus virulence. Comparative pathogenesis of a virulent strain of La Crosse and an avirulent strain of Tahyna virus","volume":"50","author":"R Janssen","year":"1984","journal-title":"Laboratory investigation; a journal of technical methods and pathology"},{"issue":"20","key":"ppat.1012530.ref022","doi-asserted-by":"crossref","first-page":"11223","DOI":"10.1128\/JVI.01093-12","article-title":"Visualizing production of beta interferon by astrocytes and microglia in brain of La Crosse virus-infected mice","volume":"86","author":"C Kallfass","year":"2012","journal-title":"Journal of virology"},{"key":"ppat.1012530.ref023","first-page":"179","article-title":"Pathology of La Crosse virus infection in humans","volume":"123","author":"B. Kalfayan","year":"1983","journal-title":"Prog Clin Biol Res"},{"issue":"2","key":"ppat.1012530.ref024","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1542\/peds.99.2.261","article-title":"Treatment of severe La Crosse encephalitis with intravenous ribavirin following diagnosis by brain biopsy","volume":"99","author":"JE McJunkin","year":"1997","journal-title":"Pediatrics"},{"key":"ppat.1012530.ref025","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1743-422X-4-41","article-title":"Genome sequence analysis of La Crosse virus and in vitro and in vivo phenotypes","volume":"4","author":"RS Bennett","year":"2007","journal-title":"Virology journal"},{"issue":"6","key":"ppat.1012530.ref026","doi-asserted-by":"crossref","first-page":"526","DOI":"10.30802\/AALAS-CM-99-990010","article-title":"Flow Rate and Apparent Volume of Cerebrospinal Fluid in Rhesus Macaques (Macaca mulatta) Based on the Pharmacokinetics of Intrathecally Administered Inulin.","volume":"70","author":"CM Lester McCully","year":"2020","journal-title":"Comparative medicine."},{"key":"ppat.1012530.ref027","article-title":"Primate brain maps: structure of the macaque brain.","author":"BD Martin RF","year":"2000","journal-title":"Amsterdam: University of Washington, Elsevier"},{"key":"ppat.1012530.ref028","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.3389\/fimmu.2020.01467","article-title":"Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases.","volume":"11","author":"SC Funes","year":"2020","journal-title":"Frontiers in immunology"},{"issue":"2","key":"ppat.1012530.ref029","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1172\/JCI28844","article-title":"Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation","volume":"117","author":"AA Chora","year":"2007","journal-title":"The Journal of clinical investigation"},{"issue":"5","key":"ppat.1012530.ref030","article-title":"Roles of Heme Oxygenase-1 in Neuroinflammation and Brain Disorders.","volume":"11","author":"YH Wu","year":"2022","journal-title":"Antioxidants (Basel)."},{"issue":"5","key":"ppat.1012530.ref031","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/bjp.2008.342","article-title":"Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders","volume":"155","author":"PJ Syapin","year":"2008","journal-title":"Br J Pharmacol"},{"issue":"12","key":"ppat.1012530.ref032","doi-asserted-by":"crossref","first-page":"e53085","DOI":"10.15252\/embr.202153085","article-title":"Adaptive homeostasis and the p53 isoform network","volume":"22","author":"S Mehta","year":"2021","journal-title":"EMBO reports"},{"issue":"9","key":"ppat.1012530.ref033","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.it.2020.07.004","article-title":"Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity","volume":"41","author":"MV Sofroniew","year":"2020","journal-title":"Trends in immunology"},{"issue":"18","key":"ppat.1012530.ref034","first-page":"6391","article-title":"Genomic analysis of reactive astrogliosis. The Journal of neuroscience: the official journal of the","volume":"32","author":"JL Zamanian","year":"2012","journal-title":"Society for Neuroscience"},{"issue":"1","key":"ppat.1012530.ref035","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1038\/s41598-017-04356-7","article-title":"Comprehensive investigation of temporal and autism-associated cell type composition-dependent and independent gene expression changes in human brains","volume":"7","author":"Q Yu","year":"2017","journal-title":"Scientific reports"},{"issue":"7","key":"ppat.1012530.ref036","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease","volume":"169","author":"H Keren-Shaul","year":"2017","journal-title":"Cell"},{"issue":"5","key":"ppat.1012530.ref037","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration","volume":"173","author":"A Deczkowska","year":"2018","journal-title":"Cell"},{"issue":"2","key":"ppat.1012530.ref038","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1089\/ars.2010.3241","article-title":"Nonhuman primate models of human immunology","volume":"14","author":"I Messaoudi","year":"2011","journal-title":"Antioxidants & redox signaling"},{"issue":"26","key":"ppat.1012530.ref039","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1016\/j.vaccine.2014.04.002","article-title":"Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN\/DEN4Delta30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine","volume":"32","author":"OA Maximova","year":"2014","journal-title":"Vaccine"},{"issue":"3","key":"ppat.1012530.ref040","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.EI10-0021-2016","article-title":"West Nile Virus Infection.","volume":"4","author":"JJ Sejvar","year":"2016","journal-title":"Microbiology spectrum"},{"issue":"3","key":"ppat.1012530.ref041","doi-asserted-by":"crossref","first-page":"807","DOI":"10.4269\/ajtmh.21-0294","article-title":"La Crosse Virus Disease in the United States, 2003\u20132019","volume":"105","author":"GM Vahey","year":"2021","journal-title":"The American journal of tropical medicine and hygiene"},{"issue":"3","key":"ppat.1012530.ref042","doi-asserted-by":"crossref","first-page":"e1114","DOI":"10.1093\/cid\/ciac403","article-title":"La Crosse Virus Neuroinvasive Disease in Children: A Contemporary Analysis of Clinical\/Neurobehavioral Outcomes and Predictors of Disease Severity.","volume":"76","author":"AE Boutzoukas","year":"2023","journal-title":"Clinical infectious diseases: an official publication of the Infectious Diseases Society of America."},{"issue":"1","key":"ppat.1012530.ref043","first-page":"25","article-title":"Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta). Immunity & ageing: I &","volume":"9","author":"ES Didier","year":"2012","journal-title":"A"},{"issue":"1","key":"ppat.1012530.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/088307389901400101","article-title":"La Crosse and other forms of California encephalitis","volume":"14","author":"RS Rust","year":"1999","journal-title":"Journal of child neurology"},{"issue":"4","key":"ppat.1012530.ref045","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/0887-8994(95)00059-O","article-title":"Infarction of basal ganglia associated with California encephalitis virus","volume":"12","author":"SM Leber","year":"1995","journal-title":"Pediatric neurology"},{"issue":"12","key":"ppat.1012530.ref046","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.3201\/eid2312.170944","article-title":"Investigation of Acute Flaccid Paralysis Reported with La Crosse Virus Infection, Ohio, USA, 2008\u20132014","volume":"23","author":"MJ Hennessey","year":"2017","journal-title":"Emerging infectious diseases"},{"key":"ppat.1012530.ref047","first-page":"16","article-title":"Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease.","volume":"8","author":"JH Jara","year":"2014","journal-title":"Frontiers in neuroanatomy."},{"issue":"2","key":"ppat.1012530.ref048","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/ar.a.10015","article-title":"Stereologic characterization and spatial distribution patterns of Betz cells in the human primary motor cortex.","volume":"270","author":"CB Rivara","year":"2003","journal-title":"The anatomical record Part A, Discoveries in molecular, cellular, and evolutionary biology."},{"issue":"18","key":"ppat.1012530.ref049","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1002\/cne.23410","article-title":"Terminal distribution of the corticospinal projection from the hand\/arm region of the primary motor cortex to the cervical enlargement in rhesus monkey","volume":"521","author":"RJ Morecraft","year":"2013","journal-title":"The Journal of comparative neurology"},{"issue":"7","key":"ppat.1012530.ref050","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/dneu.22455","article-title":"The corticospinal tract: Evolution, development, and human disorders.","volume":"77","author":"Q Welniarz","year":"2017","journal-title":"Developmental neurobiology."},{"key":"ppat.1012530.ref051","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1146\/annurev.neuro.31.060407.125547","article-title":"Descending pathways in motor control","volume":"31","author":"RN Lemon","year":"2008","journal-title":"Annual review of neuroscience"},{"issue":"3","key":"ppat.1012530.ref052","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/mus.20333","article-title":"Comparing the function of the corticospinal system in different species: organizational 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Pruitt","year":"2021","journal-title":"Current neurology and neuroscience reports"},{"key":"ppat.1012530.ref059","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3389\/fimmu.2019.00586","article-title":"Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management.","volume":"10","author":"S S\u00e1nchez-Ram\u00f3n","year":"2019","journal-title":"Frontiers in immunology"},{"key":"ppat.1012530.ref060","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev-pathol-031920-101429","article-title":"Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories.","volume":"16","author":"JL Casanova","year":"2021","journal-title":"Annual review of pathology"},{"key":"ppat.1012530.ref061","doi-asserted-by":"crossref","first-page":"827815","DOI":"10.3389\/fimmu.2021.827815","article-title":"Neuroinflammation Associated With Inborn Errors of Immunity.","volume":"12","author":"H 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