{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:46:11Z","timestamp":1781196371836,"version":"3.54.1"},"reference-count":88,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R01AI132414"],"award-info":[{"award-number":["R01AI132414"]}]},{"name":"Stead Family Foundation"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Human cytomegalovirus (HCMV) is a highly prevalent viral pathogen that typically presents asymptomatically in healthy individuals despite lifelong latency. However, in 10%\u201315% of congenital cases, this beta-herpesvirus demonstrates direct effects on the central nervous system, including microcephaly, cognitive and learning delays, and hearing deficits. HCMV has been widely shown to infect neural progenitor cells, but the permissiveness of fully differentiated neurons to HCMV is controversial and chronically understudied, despite potential associations between HCMV infection and neurodegenerative conditions. Using a model system representative of the human forebrain, we demonstrate that induced pluripotent stem cell-derived excitatory glutamatergic and inhibitory GABAergic neurons are fully permissive to HCMV with complete viral replication, competent virion production, and spread within the culture. Interestingly, while cell proliferation was not induced in these post-mitotic neurons, HCMV did increase expression of proliferative markers Ki67 and proliferative cell nuclear antigen suggesting alterations in cell cycle machinery. These findings are consistent with previous HCMV-mediated changes in various cell types and implicate the ability of viral proteins to alter proliferative pathways to promote virion production. Infection also induces significant structural changes in forebrain neurons, such as the formation of syncytia and the retraction of neurites. Finally, we demonstrate that HCMV disrupts calcium signaling and decreases neurotransmission, with action potential generation effectively silenced after 15 days post-infection. Taken together, our data highlight the potential for forebrain neurons to be permissive to HCMV infection in the central nervous system, which has significant implications for overall brain health and function.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Human cytomegalovirus (HCMV) is a highly prevalent viral pathogen that can cause serious neurological deficits in infants experiencing an\n                      <jats:italic>in utero<\/jats:italic>\n                      infection. Also, as a life-long infection, HCMV has been associated with several diseases in the adult brain. HCMV is known to infect early neural progenitor cells, but whether it also infects terminally differentiated neurons is still debated. Here, we differentiated human-induced pluripotent stem cells into neurons for 84\u2013120 days to test the ability of HCMV to infect terminally differentiated neurons and assess the downstream functional consequences. We discovered that mature human neurons are highly permissive to HCMV infection, exhibited late replication hallmarks, and produced infectious virus. Moreover, infection in terminally differentiated neurons essentially eliminated neuron function. These results demonstrate that terminally differentiated human neurons are permissive to HCMV infection, which can significantly alter both structural and functional features of this mature neuron population.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02251-23","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T09:03:18Z","timestamp":1700038998000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Human cytomegalovirus induces significant structural and functional changes in terminally differentiated human cortical neurons"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1847-3979","authenticated-orcid":false,"given":"Jacob W.","family":"Adelman","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzette","family":"Rosas-Rogers","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah L.","family":"Mokry","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-7094","authenticated-orcid":false,"given":"Scott S.","family":"Terhune","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"},{"name":"Marquette University and Medical College of Wisconsin Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9676-8548","authenticated-orcid":false,"given":"Allison D.","family":"Ebert","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00582-z"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000322141"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2034"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-022-01387-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-4-22"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit018"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02161-09"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.535"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.544"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1982.03970460032007"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000000404"},{"key":"e_1_3_3_13_2","unstructured":"Prevention. 2022. Babies born with congenital CMV on centers of disease control and prevention. Available from: https:\/\/www.cdc.gov\/cmv\/congenital-infection.html. Retrieved 8 Apr 2023."},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00268"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2016.03.006"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1086\/379711"},{"key":"e_1_3_3_17_2","first-page":"91","article-title":"Human cytomegalovirus replication and modulation of apoptosis in astrocytes","volume":"2","author":"Lokensgard JR","year":"1999","unstructured":"Lokensgard JR, Cheeran MC, Gekker G, Hu S, Chao CC, Peterson PK. 1999. Human cytomegalovirus replication and modulation of apoptosis in astrocytes. J Hum Virol 2:91\u2013101.","journal-title":"J Hum Virol"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e32836206d1"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3109\/13550289909015817"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-78-12-3349"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199107000-00005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00676-06"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00943-08"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20682"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000038"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/170.5.1267"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-022-01258-9"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049700"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00954-19"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609353103"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(87)90268-6"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-014-1445-5"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/162.6.1252"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00957-19"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu437"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit210"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096779"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1553558"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470151808.sc02d02s6"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.83286-0"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002444"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2201787119"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02630-20"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.60.2.583-588.1986"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.69.11.6697-6704.1995"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.70.12.8850-8857.1996"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.2.1629-1634.1997"},{"key":"e_1_3_3_48_2","first-page":"188","article-title":"Effects of human cytomegalovirus on the cell cycle of duct epithelial cell cultures of human salivary gland in vitro and relative mechanism","volume":"25","author":"Yang G-R","year":"2011","unstructured":"Yang G-R, Huang G-S, He X-X, Xue Y-J. 2011. Effects of human cytomegalovirus on the cell cycle of duct epithelial cell cultures of human salivary gland in vitro and relative mechanism. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 25:188\u2013190.","journal-title":"Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2015.1004937"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-020-00696-9"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199803)184:3<279::AID-PATH7>3.0.CO;2-4"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.03.015"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1186\/2042-4280-4-2"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00126-22"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.10.8503-8511.1999"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/v10020092"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.061029798"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-020-0263-5"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8040615"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13122355"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01315675"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781119467748"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000038"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011316"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11175221"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu437"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2006.00796.x"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.043"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.10.016"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.05.034"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-021-00810-w"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.817198"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03492-13"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709704104"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00696-23"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001256"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00121-16"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-015-0396-z"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00384"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100002"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.2.981-987.1997"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-65-1-55"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500803102"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01441-06"},{"key":"e_1_3_3_85_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409597102"},{"key":"e_1_3_3_86_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13101973"},{"key":"e_1_3_3_87_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2201787119"},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302679"},{"key":"e_1_3_3_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2007.02.022"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.02251-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.02251-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T15:07:08Z","timestamp":1703257628000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.02251-23"}},"subtitle":[],"editor":[{"given":"Thomas","family":"Shenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,12,19]]},"references-count":88,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,12,19]]}},"alternative-id":["10.1128\/mbio.02251-23"],"URL":"https:\/\/doi.org\/10.1128\/mbio.02251-23","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.03.03.531045","asserted-by":"object"}]},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,19]]},"assertion":[{"value":"2023-08-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02251-23"}}