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Placental trophoblasts employ specialized antiviral strategies to protect against infection while preventing maternal immune rejection of the fetus. However, the full extent of how trophoblasts respond to viral infections is not well understood. To address this, we defined the transcriptional landscape of human trophoblast organoids infected with seven diverse teratogenic viruses. We found that herpesviruses, including HSV-1, HSV-2, and HCMV, did not trigger an IFN response. Instead, they activated the expression of DUX4 and its downstream target genes: DUX4-stimulated genes (DSGs). This program was enriched in trophoblasts and associated with cells containing low HSV-1 gene expression following infection. Screening highly expressed DSGs revealed that many of them exhibited anti-herpesvirus activity, indicating they comprise an alternative antiviral pathway similar to the IFN-stimulated gene response. These findings identify DUX4 as a master regulator of an antiviral program in trophoblasts, specifically targeting a prominent family of teratogenic viruses.<\/jats:p>","DOI":"10.1084\/jem.20250448","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T06:20:47Z","timestamp":1755238847000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["DUX4-stimulated genes define an antiviral defense program in human placental trophoblasts"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3562-4166","authenticated-orcid":true,"given":"Joshua","family":"Hatterschide","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University School of Medicine 1 Department of Integrative Immunobiology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 2 , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6842-086X","authenticated-orcid":true,"given":"Liheng","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University School of Medicine 1 Department of Integrative Immunobiology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 2 , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-6309","authenticated-orcid":true,"given":"Carolyn B.","family":"Coyne","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University School of Medicine 1 Department of Integrative Immunobiology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 2 , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"2025091809522581700_bib1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat6114","article-title":"Immune responses at the maternal-fetal interface","volume":"4","author":"Ander","year":"2019","journal-title":"Sci. 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