{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:28:07Z","timestamp":1767713287930,"version":"3.41.2"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The aim of this study was to identify immune factors that distinguish patients with herpes simplex virus type 2 (HSV-2) meningitis from patients with HSV-2 genital herpes by analyzing demographic data, <jats:italic>in vitro<\/jats:italic> production of cytokines and other immune factors secreted by patient peripheral blood mononuclear cells (PBMC), and existing antibody responses. PBMC and plasma were collected from patients previously diagnosed with HSV-2 meningitis (n=49) and HSV-2 genital herpes (n=38). PBMC were cultured in the presence or absence of HSV-2 and followed by multiplex analyses of culture supernatants for a panel of immune factors including Th1 and inflammatory cytokines, interferons, and chemokines. Plasma was analyzed for type-specific HSV antibodies and HSV-2 DNA. The multivariate method OPLS-DA was used to identify immune response patterns that differentiate the two patient groups. The multivariate analysis showed that the immune profile differed significantly between the two different HSV-2 disease manifestations. Meningitis patients were distinguished by the spontaneous production of several anti-viral immune factors by PBMC including type I and type III IFNs. PBMC from HSV-2 meningitis patients also secreted significantly higher levels of IFN-\u03b3 in response to HSV-2 compared to PBMC from HSV-2 genital herpes patients. Blocking the type I IFN receptor reduced the production of HSV-2-induced IFN-\u03b3 by PBMC suggesting that enhanced production of type I IFNs could promote IFN-\u03b3 recall responses. The levels of HSV-2 type-specific antibodies did not differ between the patient groups. In conclusion, we show that HSV-2 meningitis leads to a more profound activation of both innate and acquired PBMC immune responses, compared to that of HSV-2 genital herpes. Whether these differences are the cause, or the consequence, of the different disease manifestations remains to be determined.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1515741","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:38:08Z","timestamp":1749015488000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytokine secretion patterns distinguish herpes simplex virus type 2 meningitis from herpes simplex virus type 2 genital herpes"],"prefix":"10.3389","volume":"16","author":[{"given":"Moa","family":"Bjerhem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Studahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Tunb\u00e4ck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva-Marie","family":"Boman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenny","family":"Brandstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Lingblom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Azadeh","family":"Reyahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Th\u00f6rn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3103","article-title":"Rapid host immune response and viral dynamics in herpes simplex virus-2 infection","volume":"19","author":"Schiffer","year":"2013","journal-title":"Nat Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"805","DOI":"10.2471\/BLT.07.046128","article-title":"An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection","volume":"86","author":"Looker","year":"2008","journal-title":"Bull World Health Org"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/00365540802235741","article-title":"High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm","volume":"40","author":"Franzen-Rohl","year":"2008","journal-title":"Scand J Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1177\/09564624241248874","article-title":"Seroprevalence of sexually transmitted infections over 44 years - A cross-sectional study in Sweden","volume":"35","author":"Andersson","year":"2024","journal-title":"Int J STD AIDS"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab1071","article-title":"Herpes simplex virus 2 meningitis in adults: A prospective, nationwide, population-based cohort study","volume":"75","author":"Jakobsen","year":"2022","journal-title":"Clin Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1086\/jid.2002.185.issue-8","article-title":"Seroprevalence and coinfection with herpes simplex virus type 1 and type 2 in the United States, 1988-1994","volume":"185","author":"Xu","year":"2002","journal-title":"J Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199911043411904","article-title":"A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group","volume":"341","author":"Langenberg","year":"1999","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00333-10","article-title":"Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis","volume":"18","author":"Franzen-Rohl","year":"2011","journal-title":"Clin Vaccine Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.79978-0","article-title":"CD4+ T-cell responses to herpes simplex virus type 2 (HSV-2) glycoprotein G are type-specific and differ in symptomatic and asymptomatic HSV-2 infected individuals","volume":"85","author":"Eriksson","year":"2004","journal-title":"J Gen Virol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1086\/313616","article-title":"Analysis of candidate-host immunogenetic determinants in herpes simplex virus-associated Mollaret\u2019s meningitis","volume":"30","author":"Tang","year":"2000","journal-title":"Clin Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2009.10.014","article-title":"HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration may predispose to herpes-associated recurrent lymphocytic meningitis","volume":"71","author":"Kallio-Laine","year":"2010","journal-title":"Hum Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abc2691","article-title":"Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans","volume":"5","author":"Hait","year":"2020","journal-title":"Sci Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.173066","article-title":"An IKBKE variant conferring functional cGAS\/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis","volume":"8","author":"Reyahi","year":"2023","journal-title":"JCI Insight"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa589","article-title":"Whole-exome sequencing of patients with recurrent HSV-2 lymphocytic mollaret meningitis","volume":"223","author":"Hait","year":"2021","journal-title":"J Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6802","article-title":"Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection","volume":"175","author":"Svensson","year":"2005","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"100558","DOI":"10.1016\/j.lanepe.2022.100558","article-title":"Epidemiology of herpes simplex virus type 2 in Europe: systematic review, meta-analyses, and meta-regressions","volume":"25","author":"Alareeki","year":"2023","journal-title":"Lancet Reg Health Eur"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-98-6-958","article-title":"Genital herpes simplex virus infections: clinical manifestations, course, and complications","volume":"98","author":"Corey","year":"1983","journal-title":"Ann Intern Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e16081","DOI":"10.1111\/ene.16081","article-title":"Benign recurrent lymphocytic meningitis (Mollaret\u2019s meningitis) in Denmark: a nationwide cohort study","volume":"31","author":"Petersen","year":"2024","journal-title":"Eur J Neurol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/sextrans-2016-052811","article-title":"Herpes simplex virus specific T cell response in a cohort with primary genital infection correlates inversely with frequency of subsequent recurrences","volume":"93","author":"Franzen-Rohl","year":"2017","journal-title":"Sex Transm Infect"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-121-11-199412010-00004","article-title":"Recurrence rates in genital herpes after symptomatic first-episode infection","volume":"121","author":"Benedetti","year":"1994","journal-title":"Ann Intern Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis031","article-title":"Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial","volume":"54","author":"Aurelius","year":"2012","journal-title":"Clin Infect Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00141-07","article-title":"Increased detection rate in diagnosis of herpes simplex virus type 2 meningitis by real-time PCR using cerebrospinal fluid samples","volume":"45","author":"Franzen-Rohl","year":"2007","journal-title":"J Clin Microbiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700385","article-title":"Cutting edge: genetic association between IFI16 single nucleotide polymorphisms and resistance to genital herpes correlates with IFI16 expression levels and HSV-2-induced IFN-beta expression","volume":"199","author":"Eriksson","year":"2017","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: A program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0466-2","article-title":"Interferon target-gene expression and epigenomic signatures in health and disease","volume":"20","author":"Barrat","year":"2019","journal-title":"Nat Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00829-12","article-title":"Peripheral blood CD4 T-cell and plasmacytoid dendritic cell (pDC) reactivity to herpes simplex virus 2 and pDC number do not correlate with the clinical or virologic severity of recurrent genital herpes","volume":"86","author":"Moss","year":"2012","journal-title":"J Virol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5640960","DOI":"10.1155\/2020\/5640960","article-title":"Frequent recurrences of genital herpes are associated with enhanced systemic HSV-specific T cell response","volume":"2020","author":"Holub","year":"2020","journal-title":"Can J Infect Dis Med Microbiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2020-000463","article-title":"Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies","volume":"8","author":"Stockfelt","year":"2021","journal-title":"Lupus Sci Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.5.1655","article-title":"Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells","volume":"178","author":"Brinkmann","year":"1993","journal-title":"J Exp Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3818","article-title":"Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation","volume":"18","author":"Park","year":"2017","journal-title":"Nat Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3201\/eid1507.080716","article-title":"Recurrent lymphocytic meningitis positive for herpes simplex virus type 2","volume":"15","author":"Kallio-Laine","year":"2009","journal-title":"Emerg Infect Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1515741\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:38:09Z","timestamp":1749015489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1515741\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2025.1515741"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1515741","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"article-number":"1515741"}}