{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:35:48Z","timestamp":1787909748694,"version":"build-2784847793"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurologic Disorders and Stroke","doi-asserted-by":"publisher","award":["K08 NS109332"],"award-info":[{"award-number":["K08 NS109332"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurologic Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS110631"],"award-info":[{"award-number":["R01 NS110631"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI163217"],"award-info":[{"award-number":["R01 AI163217"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI140443"],"award-info":[{"award-number":["R21 AI140443"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["F30 AI150049"],"award-info":[{"award-number":["F30 AI150049"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 AI147714"],"award-info":[{"award-number":["R21 AI147714"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI098681"],"award-info":[{"award-number":["P01 AI098681"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI139618"],"award-info":[{"award-number":["R01 AI139618"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ann and Robert H. Lurie Children's Hospital of Chicago"},{"name":"Children\u2019s Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Herpes simplex virus (HSV) infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow varied clinical courses, with approximately half of infants experiencing only external infection of the skin rather than invasive neurologic disease. Understanding the cause of these divergent outcomes is essential to developing neuroprotective strategies. To directly assess the contribution of viral variation to neurovirulence, independent of human host factors, we evaluated clinical HSV isolates from neonates with different neurologic outcomes in neurologically relevant in vitro and in vivo models. We found that isolates taken from neonates with encephalitis are more neurovirulent in human neuronal culture and mouse models of HSV encephalitis, as compared to isolates collected from neonates with skin-limited disease. These findings suggest that inherent characteristics of the infecting HSV strain contribute to disease outcome following neonatal infection.<\/jats:p>","DOI":"10.1093\/infdis\/jiac151","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T07:13:16Z","timestamp":1650525196000},"page":"1499-1509","source":"Crossref","is-referenced-by-count":9,"title":["Herpes Simplex Virus-2 Variation Contributes to Neurovirulence During Neonatal Infection"],"prefix":"10.1093","volume":"226","author":[{"given":"Cooper K","family":"Hayes","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine , Chicago, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher K","family":"Villota","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases, Ann and Robert H. Lurie Children\u2019s Hospital of Chicago , Chicago, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona B","family":"McEnany","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, New Hampshire , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Cer\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, New Hampshire , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-1678","authenticated-orcid":false,"given":"Moriah L","family":"Szpara","sequence":"additional","affiliation":[{"name":"Departments of Biology, Biochemistry, and Molecular Biology, Center for Infectious Disease Dynamics and the Huck Institutes of the Life Sciences, Pennsylvania State University , University Park, Pennsylvania , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey M","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Leib","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, New Hampshire , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Longnecker","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine , Chicago, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D","family":"Weitzman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Division of Protective Immunity, Children\u2019s Hospital of Philadelphia , Philadelphia, Pennsylvania , USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-4185","authenticated-orcid":false,"given":"Lisa N","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases, Ann and Robert H. Lurie Children\u2019s Hospital of Chicago , Chicago, Illinois , USA"},{"name":"Department of Pediatrics, Northwestern University Feinberg School of Medicine , Chicago, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"2023060109483356500_jiac151-B1","doi-asserted-by":"crossref","first-page":"e300","DOI":"10.1016\/S2214-109X(16)30362-X","article-title":"First estimates of the global and regional incidence of neonatal herpes infection","volume":"5","author":"Looker","year":"2017","journal-title":"Lancet Glob Health"},{"key":"2023060109483356500_jiac151-B2","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1053\/j.semperi.2018.02.004","article-title":"Neonatal herpes simplex virus infections","volume":"42","author":"Pinninti","year":"2018","journal-title":"Semin Perinatol"},{"key":"2023060109483356500_jiac151-B3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/infdis\/158.1.109","article-title":"Changing presentation of herpes simplex virus infection in neonates","volume":"158","author":"Whitley","year":"1988","journal-title":"J Infect Dis"},{"key":"2023060109483356500_jiac151-B4","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1542\/peds.108.2.230","article-title":"Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections","volume":"108","author":"Kimberlin","year":"2001","journal-title":"Pediatrics"},{"key":"2023060109483356500_jiac151-B5","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1056\/NEJM199102143240704","article-title":"Predictors of morbidity and mortality in neonates with herpes simplex virus infections","volume":"324","author":"Whitley","year":"1991","journal-title":"N Engl J Med"},{"key":"2023060109483356500_jiac151-B6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1542\/peds.108.2.223","article-title":"Natural history of neonatal herpes simplex virus infections in the acyclovir era","volume":"108","author":"Kimberlin","year":"2001","journal-title":"Pediatrics"},{"key":"2023060109483356500_jiac151-B7","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1056\/NEJMoa1003509","article-title":"Oral acyclovir suppression and neurodevelopment after neonatal herpes","volume":"365","author":"Kimberlin","year":"2011","journal-title":"N Engl J Med"},{"key":"2023060109483356500_jiac151-B8","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1126\/science.1128346","article-title":"Herpes simplex virus encephalitis in human UNC-93B deficiency","volume":"314","author":"Casrouge","year":"2006","journal-title":"Science"},{"key":"2023060109483356500_jiac151-B9","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"key":"2023060109483356500_jiac151-B10","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1212\/WNL.0000000000000999","article-title":"TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk","volume":"83","author":"Lim","year":"2014","journal-title":"Neurology"},{"key":"2023060109483356500_jiac151-B11","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1172\/JCI44947","article-title":"Virulence determinants of pandemic influenza viruses","volume":"121","author":"Tscherne","year":"2011","journal-title":"J Clin Invest"},{"key":"2023060109483356500_jiac151-B12","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3390\/v3030204","article-title":"A strong case for viral genetic factors in HIV virulence","volume":"3","author":"M\u00fcller","year":"2011","journal-title":"Viruses"},{"key":"2023060109483356500_jiac151-B13","doi-asserted-by":"crossref","first-page":"e00590-18","DOI":"10.1128\/mSphere.00590-18","article-title":"Genotypic and phenotypic diversity of herpes simplex virus 2 within the infected neonatal population","volume":"4","author":"Akhtar","year":"2019","journal-title":"mSphere"},{"key":"2023060109483356500_jiac151-B14","doi-asserted-by":"crossref","first-page":"a004382","DOI":"10.1101\/mcs.a004382","article-title":"Personalized viral genomic investigation of herpes simplex virus 1 perinatal viremic transmission with dual fatality","volume":"5","author":"Shipley","year":"2018","journal-title":"Cold Spring Harb Mol Case Stud"},{"key":"2023060109483356500_jiac151-B15","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/infdis\/jiy216","article-title":"Genome-wide surveillance of genital herpes simplex virus type 1 from multiple anatomic sites over time","volume":"218","author":"Shipley","year":"2018","journal-title":"J Infect Dis"},{"key":"2023060109483356500_jiac151-B16","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1128\/JVI.01987-13","article-title":"Evolution and diversity in human herpes simplex virus genomes","volume":"88","author":"Szpara","year":"2014","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B17","doi-asserted-by":"crossref","first-page":"e00942-17","DOI":"10.1128\/JVI.00942-17","article-title":"Molecular evolution of herpes simplex virus 2 complete genomes: comparison between primary and recurrent infections","volume":"91","author":"Minaya","year":"2017","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B18","doi-asserted-by":"crossref","first-page":"e1003735","DOI":"10.1371\/journal.pgen.1003735","article-title":"Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection","volume":"9","author":"Renzette","year":"2013","journal-title":"PLoS Genet"},{"key":"2023060109483356500_jiac151-B19","doi-asserted-by":"crossref","first-page":"8219","DOI":"10.1128\/JVI.01303-15","article-title":"Genome sequencing and analysis of geographically diverse clinical isolates of herpes simplex virus 2","volume":"89","author":"Newman","year":"2015","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B20","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1056\/NEJM199102143240703","article-title":"A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection","volume":"324","author":"Whitley","year":"1991","journal-title":"N Engl J Med"},{"key":"2023060109483356500_jiac151-B21","doi-asserted-by":"crossref","first-page":"e02210-18","DOI":"10.1128\/JVI.02210-18","article-title":"Lund human mesencephalic (LUHMES) neuronal cell line supports herpes simplex virus 1 latency in vitro","volume":"93","author":"Edwards","year":"2019","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B22","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/j.1471-4159.2011.07255.x","article-title":"Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line","volume":"119","author":"Scholz","year":"2011","journal-title":"J Neurochem"},{"key":"2023060109483356500_jiac151-B23","doi-asserted-by":"crossref","first-page":"e1009285","DOI":"10.1371\/journal.ppat.1009285","article-title":"ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis","volume":"17","author":"Hayes","year":"2021","journal-title":"PLoS Pathog"},{"key":"2023060109483356500_jiac151-B24","doi-asserted-by":"crossref","first-page":"e00921-20","DOI":"10.1128\/mBio.00921-20","article-title":"The innate immune response to herpes simplex virus 1 infection is dampened in the newborn brain and can be modulated by exogenous interferon beta to improve survival","volume":"11","author":"Giraldo","year":"2020","journal-title":"mBio"},{"key":"2023060109483356500_jiac151-B25","doi-asserted-by":"crossref","first-page":"e1004580","DOI":"10.1371\/journal.ppat.1004580","article-title":"Differential reliance on autophagy for protection from HSV encephalitis between newborns and adults","volume":"11","author":"Wilcox","year":"2015","journal-title":"PLoS Pathog"},{"key":"2023060109483356500_jiac151-B26","doi-asserted-by":"crossref","first-page":"e6937","DOI":"10.1073\/pnas.1513045112","article-title":"HSV targeting of the host phosphatase PP1\u03b1 is required for disseminated disease in the neonate and contributes to pathogenesis in the brain","volume":"112","author":"Wilcox","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023060109483356500_jiac151-B27","doi-asserted-by":"crossref","first-page":"eaau6039","DOI":"10.1126\/scitranslmed.aau6039","article-title":"Maternal immunization confers protection against neonatal herpes simplex mortality and behavioral morbidity","volume":"11","author":"Patel","year":"2019","journal-title":"Sci Transl Med"},{"key":"2023060109483356500_jiac151-B28","doi-asserted-by":"crossref","first-page":"e00958-17","DOI":"10.1128\/JVI.00958-17","article-title":"Differentiated human SH-SY5Y cells provide a reductionist model of herpes simplex virus 1 neurotropism","volume":"91","author":"Shipley","year":"2017","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B29","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1084\/jem.119.2.343","article-title":"The pathogenesis of herpes virus encephalitis","volume":"119","author":"Johnson","year":"1964","journal-title":"J Exp Med"},{"key":"2023060109483356500_jiac151-B30","doi-asserted-by":"crossref","first-page":"e332","DOI":"10.1002\/cpz1.332","article-title":"Guinea pig and mouse models for genital herpes infection","volume":"1","author":"Hook","year":"2021","journal-title":"Curr Protoc"},{"key":"2023060109483356500_jiac151-B31","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1128\/jvi.76.5.2199-2205.2002","article-title":"Altering the expression kinetics of VP5 results in altered virulence and pathogenesis of herpes simplex virus type 1 in mice","volume":"76","author":"Tran","year":"2002","journal-title":"J Virol"},{"key":"2023060109483356500_jiac151-B32","first-page":"599","article-title":"HSV-1 thymidine kinase promotes virulence and latency in the mouse","volume":"24","author":"Gordon","year":"1983","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2023060109483356500_jiac151-B33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1046\/j.1460-9568.2002.02057.x","article-title":"Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain","volume":"16","author":"Boivin","year":"2002","journal-title":"Eur J Neurosci"},{"key":"2023060109483356500_jiac151-B34","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.3390\/v13122542","article-title":"Distinguishing features common to dual fatal herpes simplex virus infections that occur in both a pregnant woman and her newborn infant","volume":"13","author":"Price","year":"2021","journal-title":"Viruses"},{"key":"2023060109483356500_jiac151-B35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1001\/jama.289.2.203","article-title":"Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant","volume":"289","author":"Brown","year":"2003","journal-title":"JAMA"},{"key":"2023060109483356500_jiac151-B36","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s40588-019-00131-6","article-title":"Viral genetic diversity and its potential contributions to the development and progression of neonatal herpes simplex virus (HSV) disease","volume":"6","author":"Akhtar","year":"2019","journal-title":"Curr Clin Microbiol Rep"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiac151\/43858854\/jiac151.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/226\/9\/1499\/50499156\/jiac151.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/226\/9\/1499\/50499156\/jiac151.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T03:53:48Z","timestamp":1700452428000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/226\/9\/1499\/6572279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,22]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,4,22]]},"published-print":{"date-parts":[[2022,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiac151","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,11,1]]},"published":{"date-parts":[[2022,4,22]]}}}