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Progress in understanding the virus and host factors involved in neonatal HSE has been hampered by the limitations of current brain models that do not fully recapitulate the tissue structure and cell composition of the developing human brain in health and disease. Here, we developed a human fetal organotypic brain slice culture (hfOBSC) model and determined its value in mimicking the HSE neuropathology in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cell viability and tissues integrity were determined by lactate dehydrogenase release in supernatant and immunohistological (IHC) analyses. Brain slices were infected with green fluorescent protein (GFP-) expressing HSV-1 and HSV-2. Virus replication and spread were determined by confocal microscopy, PCR and virus culture. Expression of pro-inflammatory cytokines and chemokines were detected by PCR. Cell tropism and HSV-induced neuropathology were determined by IHC analysis. Finally, the in situ data of HSV-infected hfOBSC were compared to the neuropathology detected in human HSE brain sections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Slicing and serum-free culture conditions were optimized to maintain the viability and tissue architecture of ex vivo human fetal brain slices for at least 14\u00a0days at 37\u00a0\u00b0C in a CO\n                      <jats:sub>2<\/jats:sub>\n                      incubator. The hfOBSC supported productive HSV-1 and HSV-2 infection, involving predominantly infection of neurons and astrocytes, leading to expression of pro-inflammatory cytokines and chemokines. Both viruses induced programmed cell death\u2014especially necroptosis\u2014in infected brain slices at later time points after infection. The virus spread, cell tropism and role of programmed cell death in HSV-induced cell death resembled the neuropathology of HSE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We developed a novel human brain culture model in which the viability of the major brain-resident cells\u2014including neurons, microglia, astrocytes and oligodendrocytes\u2014and the tissue architecture is maintained for at least 2\u00a0weeks in vitro under serum-free culture conditions. The close resemblance of cell tropism, spread and neurovirulence of HSV-1 and HSV-2 in the hfOBSC model with the neuropathological features of human HSE cases underscores its potential to detail the pathophysiology of other neurotropic viruses and as preclinical model to test novel therapeutic interventions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-024-03027-5","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T05:04:17Z","timestamp":1706763857000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Herpes simplex virus infection induces necroptosis of neurons and astrocytes in human fetal organotypic brain slice cultures"],"prefix":"10.1186","volume":"21","author":[{"given":"Ahmad S.","family":"Rashidi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana N.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caithlin R.","family":"Peelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"van Gent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner J. 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The brain samples were provided by the BioBank of the Amsterdam University Medical Center (Amsterdam, The Netherlands). According to the institutional \u201cOpt\u2010Out\u201d system, which is defined by the National \u201cCode of Good Conduct\u201d [Dutch: Code Goed Gebruik, May 2011], these surplus human brain tissues were made available for the current study. Human fetal brain tissue was obtained from legally terminated second trimester pregnancies (17\u201320\u00a0weeks) by the HIS-Mouse Facility of Academic Medical Center (AMC; Amsterdam, The Netherlands), after written informed consent of the mother for the tissue\u2019s use in research and with approval of the Medical Ethical Review Board of the AMC (MEC-2003-038) and the Erasmus MC (MEC-2017-009). Study procedures were performed according to the Declaration of Helsinki, and in compliance with relevant Dutch laws and institutional guidelines. The fetal brain tissues obtained were anonymized and non-traceable to the donor. On request by the researchers, only gender and gestational age were provided.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests\u00a0"}}],"article-number":"38"}}