{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:46:32Z","timestamp":1774928792125,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thelma Pyne Postdoctoral Award","award":["PS64847"],"award-info":[{"award-number":["PS64847"]}]},{"name":"Thelma Pyne Postdoctoral Award","award":["RG192195"],"award-info":[{"award-number":["RG192195"]}]},{"name":"Australia\u2013Germany Joint Research Cooperation Scheme","award":["PS64847"],"award-info":[{"award-number":["PS64847"]}]},{"name":"Australia\u2013Germany Joint Research Cooperation Scheme","award":["RG192195"],"award-info":[{"award-number":["RG192195"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.<\/jats:p>","DOI":"10.3390\/v16060918","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:50:09Z","timestamp":1717588209000},"page":"918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5926-7082","authenticated-orcid":false,"given":"Ece","family":"Egilmezer","sequence":"first","affiliation":[{"name":"Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney 2031, Australia"},{"name":"School of Clinical Medicine, University of New South Wales, Kensington 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart T.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney 2031, Australia"},{"name":"School of Clinical Medicine, University of New South Wales, Kensington 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glen","family":"Lauw","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmine","family":"Follett","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Sonntag","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Sch\u00fctz","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Marschall","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0988-7827","authenticated-orcid":false,"given":"William D.","family":"Rawlinson","sequence":"additional","affiliation":[{"name":"Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney 2031, Australia"},{"name":"School of Clinical Medicine, University of New South Wales, Kensington 2052, Australia"},{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/rmv.535","article-title":"Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection","volume":"17","author":"Kenneson","year":"2007","journal-title":"Rev. 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