Manja Idorn, Xiangning Ding, Stefanie Fruhwürth, Søren Holste, Line S Reinert, Christian S Skoven, Katarina Türner-Stenström, Alexander Schmitz, Mikkel H Vendelbo, Benedicte P Ulhøi, Dzeneta Vizlin-Hodzic, Mona Wefelmeyer, Ryo Narita, Lona J Kroese, Ivo J Huijbers, Michelle Møhlenberg, Anne Kruse Hollensen, Xin Lai, Marie B Iversen, Brian Hansen, Trine H Mogensen, Søren R Paludan
{"title":"Role for NF-κB in herpes encephalitis pathology in mice genocopying an inborn error of IRF3-IFN immunity.","authors":"Manja Idorn, Xiangning Ding, Stefanie Fruhwürth, Søren Holste, Line S Reinert, Christian S Skoven, Katarina Türner-Stenström, Alexander Schmitz, Mikkel H Vendelbo, Benedicte P Ulhøi, Dzeneta Vizlin-Hodzic, Mona Wefelmeyer, Ryo Narita, Lona J Kroese, Ivo J Huijbers, Michelle Møhlenberg, Anne Kruse Hollensen, Xin Lai, Marie B Iversen, Brian Hansen, Trine H Mogensen, Søren R Paludan","doi":"10.1084/jem.20250064","DOIUrl":"https://doi.org/10.1084/jem.20250064","url":null,"abstract":"<p><p>Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1-induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-κB activation. NF-κB inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-κB-driven immunopathology, offering insights with therapeutic potential.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"223 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Xu, Zheqi Zhou, Wenzheng Chen, Fei Du, Sanling Huang, Jinhui Qi, Yuwen Zeng, Hao Su, Jiaxin Wang, Chunfu Xiao, Xiaoyu Zhao, Xiaoge Liu, Yang Feng, Chuan-Yun Li, Fan Wang, Zhaofei Liu, Yunjia Zhang, Zhi Peng, Zhaode Bu, Yang-Xin Fu, Ziyu Li, Di Wang, Chuanhui Han
{"title":"Tumors with microsatellite instability upregulate TREX1 to escape antitumor immunity.","authors":"Yan Xu, Zheqi Zhou, Wenzheng Chen, Fei Du, Sanling Huang, Jinhui Qi, Yuwen Zeng, Hao Su, Jiaxin Wang, Chunfu Xiao, Xiaoyu Zhao, Xiaoge Liu, Yang Feng, Chuan-Yun Li, Fan Wang, Zhaofei Liu, Yunjia Zhang, Zhi Peng, Zhaode Bu, Yang-Xin Fu, Ziyu Li, Di Wang, Chuanhui Han","doi":"10.1084/jem.20250265","DOIUrl":"https://doi.org/10.1084/jem.20250265","url":null,"abstract":"<p><p>Currently, it remains largely unclear how MSI-H/dMMR tumors, despite heightened immune pathway activation and antigenic mutation accumulation, evade immune elimination and promote tumorigenesis. Our study showed that dMMR tumors accumulate cytosolic double-stranded DNA, activating the cGAS-IFN pathway and upregulating DNA-digesting enzyme TREX1. In immunocompetent mice, Trex1 depletion in MSI-H/dMMR tumors abolished tumor formation in a CD8+ T cell-dependent manner, suggesting its critical role in enabling these tumors to evade immune attack. Mechanistically, Trex1 loss amplified tumor-intrinsic cGAS-STING signaling, promoted the activation of CD8+ T cells, and triggered systemic antitumor immunity. Critically, ablating cGAS-STING signaling in MSI-H/dMMR tumors abolished the immune boost from TREX1 deletion, revealing the critical role MSI-H/dMMR tumor-intrinsic cGAS-STING pathway. Furthermore, Trex1 inhibition specifically reduced MSI-H/dMMR tumors growth in vivo, highlighting its clinical potential. Together, we identify the cGAS-STING-TREX1 loop as a key immune escape mechanism in MSI-H/dMMR cancers, suggesting TREX1 inhibition could enhance immunotherapy for these patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William J Branchett, Evangelos Stavropoulos, Jessica Shields, Alaa Al-Dibouni, Marcos Cardoso, Ana Isabel Fernandes, Lúcia Moreira-Teixeira, Hubert Slawinski, Anna Mikolajczak, Angela Rodgers, Margarida Saraiva, Anne O'Garra
{"title":"Type I IFN drives neutrophil swarming, impeding lung T cell-macrophage interactions and TB control.","authors":"William J Branchett, Evangelos Stavropoulos, Jessica Shields, Alaa Al-Dibouni, Marcos Cardoso, Ana Isabel Fernandes, Lúcia Moreira-Teixeira, Hubert Slawinski, Anna Mikolajczak, Angela Rodgers, Margarida Saraiva, Anne O'Garra","doi":"10.1084/jem.20250466","DOIUrl":"10.1084/jem.20250466","url":null,"abstract":"<p><p>The early immune mechanisms determining Mycobacterium tuberculosis infection outcome are unclear. Using bulk and scRNA-seq over the first weeks of infection, we describe an unexpected, higher early pulmonary type I IFN response in relatively resistant C57BL/6 as compared with highly TB-susceptible C3HeB/FeJ mice. C57BL/6 mice showed pronounced early monocyte-derived macrophage (MDM) accumulation and extensive CD4+ T cell-MDM interactions in lung lesions, accompanied by high expression of T cell-attractant chemokines by MDMs. Conversely, lesions in C3HeB/FeJ mice were dominated by neutrophils with high expression of pro-inflammatory chemokines, from which CD4+ T cells were spatially segregated. Early type I IFN signaling blockade reduced bacterial load and neutrophil swarming within early TB lesions while increasing CD4+ T cell numbers in both C57BL/6 and C3HeB/FeJ mice, with later more pronounced effects on bacterial load in C3HeB/FeJ mice. These data suggest that early type I IFN signaling during M. tuberculosis infection favors neutrophil accumulation and limits CD4+ T cell infiltration into developing lesions.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qing Chang, Li Ma, Ziying Lin, Yang Shu, Pao-Fen Ko, Matthew Blumberg, Jian-Fu Chen
{"title":"Identification of lymphatic vessels in skull periosteum but not bone marrow reveals skull channel heterogeneity.","authors":"Qing Chang, Li Ma, Ziying Lin, Yang Shu, Pao-Fen Ko, Matthew Blumberg, Jian-Fu Chen","doi":"10.1084/jem.20241971","DOIUrl":"10.1084/jem.20241971","url":null,"abstract":"<p><p>Whether and where lymphatic vessels occur in bone or bone marrow is unclear. The heterogeneity of skull channels and bone marrow remains poorly understood. Here, we used organ clearing, high-resolution three-dimensional imaging, cell type-specific mouse genetics, and surgical approaches to investigate skull vasculatures. We identified lymphatic vessels at the skull periosteum and found no evidence of lymphatic vessels in the cortical bones or skull bone marrow, where the lymphatic marker VEGFR3 labels blood vessels. Skull periosteum channels to the upper skin are found to occur more frequently in the parietal bone than the interparietal bone, whereas bone marrow is found more often in the interparietal bone than the parietal bone. Despite skull bone marrow expansion during aging, skull channels are significantly reduced, suggesting the aging-dependent uncoupling of skull channels and bone marrow. Together, our findings show lymphatic vessels are present in the skull periosteum but absent in bone marrow, with channel and bone marrow heterogeneity varying by skull region and age.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12447874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siriruk Changrob, Atsuhiro Yasuhara, Suncheol Park, Sandhya Bangaru, Lei Li, Chloe A Troxell, Peter J Halfmann, Steven A Erickson, Nicholas J Catanzaro, Meng Yuan, Panpan Zhou, Min Huang, G Dewey Wilbanks, Joshua J C McGrath, Gagandeep Singh, Sean A Nelson, Yanbin Fu, Nai-Ying Zheng, Sofia M Carayannopoulos, Haley L Dugan, Dustin G Shaw, Christopher T Stamper, Maria Lucia L Madariaga, Florian Krammer, Raiees Andrabi, Dennis R Burton, Andrew B Ward, Ian A Wilson, Yoshihiro Kawaoka, Patrick C Wilson
{"title":"Common cold embecovirus imprinting primes broadly neutralizing antibody responses to SARS-CoV-2 S2.","authors":"Siriruk Changrob, Atsuhiro Yasuhara, Suncheol Park, Sandhya Bangaru, Lei Li, Chloe A Troxell, Peter J Halfmann, Steven A Erickson, Nicholas J Catanzaro, Meng Yuan, Panpan Zhou, Min Huang, G Dewey Wilbanks, Joshua J C McGrath, Gagandeep Singh, Sean A Nelson, Yanbin Fu, Nai-Ying Zheng, Sofia M Carayannopoulos, Haley L Dugan, Dustin G Shaw, Christopher T Stamper, Maria Lucia L Madariaga, Florian Krammer, Raiees Andrabi, Dennis R Burton, Andrew B Ward, Ian A Wilson, Yoshihiro Kawaoka, Patrick C Wilson","doi":"10.1084/jem.20251146","DOIUrl":"10.1084/jem.20251146","url":null,"abstract":"<p><p>The S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is highly conserved across coronavirus strains and therefore is a potential pan-coronavirus vaccine target. However, antibodies targeting this region are typically non-neutralizing. We report herein that S2-targeting antibodies from patients who recovered from SARS-CoV-2 infection bound only closely related sarbecovirus subgenus strains and, like most known S2 antibodies, none of these were neutralizing. In contrast, first-exposure, severe acutely infected COVID-19 patients predominantly induced back-boosted antibody-secreting cells imprinted against past common cold coronavirus strain OC43 that were cross-reactive to as many as five subgenera of betacoronavirus strains and gave rise to antibodies that were neutralizing and protective. The antibodies targeted two different sites: one defined by competition with stem helix antibodies, and the second to an underdescribed epitope at the apex of S2. These findings suggest that S2-targeted vaccines could strategically exploit controlled OC43 priming followed by SARS-CoV-2 boosting to enhance the breadth and quality of protective antibody responses.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tao Han, Chenchen Ruan, Huiyong Lin, Yuxia Zhang, Lang Li, Ye-Hsuan Sun, Chuan-Qi Zhong, Xin Chen, Kai Huang, Yating Cao, Zusen Fan, Hongbing Zhang, Jiahuai Han, Yingying Zhang
{"title":"RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice.","authors":"Tao Han, Chenchen Ruan, Huiyong Lin, Yuxia Zhang, Lang Li, Ye-Hsuan Sun, Chuan-Qi Zhong, Xin Chen, Kai Huang, Yating Cao, Zusen Fan, Hongbing Zhang, Jiahuai Han, Yingying Zhang","doi":"10.1084/jem.20250277","DOIUrl":"https://doi.org/10.1084/jem.20250277","url":null,"abstract":"<p><p>Excess TNF causes systemic inflammatory response syndrome and mortality. RIPK1 coordinates TNF signaling through kinase-dependent and -independent mechanisms. S161 autophosphorylation is a primary function of RIPK1 kinase activity in vitro, and here we show that it is sufficient to mediate RIPK1 kinase-dependent function in vivo. S161 phospho-mimic mutation (S161E) effectively overcomes chemical or genetic inhibition of RIPK1 kinase activity in TNF-treated cells and mice. Mechanistically, S161 autophosphorylation is necessary for further autophosphorylation in RIPK1, including at S166. Ripk1S161E/S161E mice are hypersensitive to TNF, enabling us to observe low-dose TNF-induced necroptosis in cecal intestinal epithelial cells (IECs) and endothelial cells (ECs) and uncover a reciprocal enhancement between IEC and EC necroptosis and a selective increase of IL-6 in the circulation by necroptosis. IL-6 promotes cecal edema and synergizes with IEC and EC necroptosis, causing cecal damage and mouse death. Our data elucidate a mechanism of RIPK1 kinase-dependent function in TNF signaling and its role in cecal pathology and mouse mortality.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kaiwen Zhu, Jiayu Dou, Bin Li, Jin Qian, Ming-Chao Zhong, Zhenghai Tang, Yan Lu, André Veillette
{"title":"CD2 and its ligands are involved in development and activation of MAIT cells.","authors":"Kaiwen Zhu, Jiayu Dou, Bin Li, Jin Qian, Ming-Chao Zhong, Zhenghai Tang, Yan Lu, André Veillette","doi":"10.1084/jem.20250431","DOIUrl":"https://doi.org/10.1084/jem.20250431","url":null,"abstract":"<p><p>MAIT cells are innate-like T cells known for their semi-invariant TCR that recognizes vitamin B metabolites presented by MR1. While the involvement of TCR and cytokines in development and activation of MAIT cells is well documented, the contribution of co-receptors, including SLAM family receptors, remains poorly understood. This study revealed that CD2 and its ligands, CD48 in mice and CD58 in humans, were crucial for MAIT cell maturation and antigen-driven activation, but not for their responses to cytokines. Cis interactions of CD2 with its ligands on the same cell were essential for activation, with trans interactions contributing in some contexts. A natural subset of human MAIT cells lacking CD2 displayed reduced activation responses to antigen. Human CD48 recognized 2B4 rather than CD2, dampening TCR signal strength and activation of human MAIT cells. Thus, the interplay between CD2 and its ligands is pivotal for MAIT cell development and activation, highlighting potential approaches for treating human diseases implicating MAIT cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Volodymyr Stetsenko, Daniel P Gail, Scott M Reba, Vinicius G Suzart, Robert Schauner, Avinaash K Sandhu, Alessandro Sette, Mohammad Haj Dezfulian, Cecilia S Lindestam Arlehamn, Stephen M Carpenter
{"title":"Human CD4+ T cells recognize Mycobacterium tuberculosis-infected macrophages amid broader responses.","authors":"Volodymyr Stetsenko, Daniel P Gail, Scott M Reba, Vinicius G Suzart, Robert Schauner, Avinaash K Sandhu, Alessandro Sette, Mohammad Haj Dezfulian, Cecilia S Lindestam Arlehamn, Stephen M Carpenter","doi":"10.1084/jem.20250460","DOIUrl":"10.1084/jem.20250460","url":null,"abstract":"<p><p>CD4+ T cell-mediated control of tuberculosis (TB) requires recognition of macrophages infected with Mycobacterium tuberculosis (Mtb). Yet, not all Mtb-specific T cells recognize infected macrophages. Using infected monocyte-derived macrophages and autologous memory CD4+ T cells from individuals with stable latent Mtb infection (LTBI), we quantify the frequency of activated T cells. T cell antigen receptor (TCR) sequencing revealed >70% of unique and >90% of total Mtb-specific TCR clonotypes in LTBI are linked to recognition of infected macrophages, while a subset required exogenous antigen exposure, suggesting incomplete recognition. Clonotypes specific for multiple Mtb antigens, and other pathogens, were identified. Remarkably, antigen screening revealed all TCRs to be specific for type VII secretion system (T7SS) substrates. Mtb-specific clonotypes expressed signature effector functions dominated by IFNγ, TNF, IL-2, and GM-CSF or chemokine production and signaling. We propose that TB vaccines, which elicit T cells specific for T7SS substrates, recognize infected macrophages, and express canonical effector functions, will offer protection against TB.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra Florescu, Michelle Zuo, Angela A Wang, Kevin Champagne-Jorgensen, Mohammed A Noor, Lesley A Ward, Erwin van Puijenbroek, Christian Klein, Jennifer L Gommerman
{"title":"Dynamic alterations of dural and bone marrow B cells in an animal model of progressive multiple sclerosis.","authors":"Alexandra Florescu, Michelle Zuo, Angela A Wang, Kevin Champagne-Jorgensen, Mohammed A Noor, Lesley A Ward, Erwin van Puijenbroek, Christian Klein, Jennifer L Gommerman","doi":"10.1084/jem.20241255","DOIUrl":"https://doi.org/10.1084/jem.20241255","url":null,"abstract":"<p><p>In multiple sclerosis (MS), the leptomeninges (LM) are populated with immune cell aggregates that correlate with disease progression. The impact of LM inflammation on the adjacent dura is largely unknown. Using a mouse model of MS that induces brain LM inflammation and age-dependent disease progression, we found that encephalitogenic T cells and B220high B cells accumulate substantially in the brain LM and parenchyma of both young and aged mice, while the adjacent dura remains relatively inert. We also observed a population of anti-CD20-resistant B220low B cells in the dura and bone marrow that virtually disappear at disease onset and accumulate in the brain of young mice concomitant with disease remission. In contrast, aged mice show a paucity of brain-resident B220low B cells at the expense of class-switched B220high B cells accompanied by severe, chronic disease. In summary, dynamic changes in the brain, LM, and dural B cells are associated with age-dependent disease severity in an animal model of progressive MS.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"DUX4-stimulated genes define an antiviral defense program in human placental trophoblasts.","authors":"Joshua Hatterschide, Liheng Yang, Carolyn B Coyne","doi":"10.1084/jem.20250448","DOIUrl":"10.1084/jem.20250448","url":null,"abstract":"<p><p>The placenta combats mother-to-fetus transmission of viruses through the antiviral activities of fetal-derived trophoblasts. 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.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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