Journal of Experimental Medicine最新文献_第4页

High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children. 病毒和细菌病原体的高负担促使儿童鼻腔先天免疫力增强。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-01 DOI: 10.1084/jem.20230911

Timothy A Watkins, Alex B Green, Julien A R Amat, Nagarjuna R Cheemarla, Katrin Hänsel, Richard Lozano, Sarah N Dudgeon, Gregory Germain, Marie L Landry, Wade L Schulz, Ellen F Foxman

{"title":"High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children.","authors":"Timothy A Watkins, Alex B Green, Julien A R Amat, Nagarjuna R Cheemarla, Katrin Hänsel, Richard Lozano, Sarah N Dudgeon, Gregory Germain, Marie L Landry, Wade L Schulz, Ellen F Foxman","doi":"10.1084/jem.20230911","DOIUrl":"10.1084/jem.20230911","url":null,"abstract":"Studies during the COVID-19 pandemic showed that children had heightened nasal innate immune responses compared with adults. To evaluate the role of nasal viruses and bacteria in driving these responses, we performed cytokine profiling and comprehensive, symptom-agnostic testing for respiratory viruses and bacterial pathobionts in nasopharyngeal samples from children tested for SARS-CoV-2 in 2021-22 (n = 467). Respiratory viruses and/or pathobionts were highly prevalent (82% of symptomatic and 30% asymptomatic children; 90 and 49% for children <5 years). Virus detection and load correlated with the nasal interferon response biomarker CXCL10, and the previously reported discrepancy between SARS-CoV-2 viral load and nasal interferon response was explained by viral coinfections. Bacterial pathobionts correlated with a distinct proinflammatory response with elevated IL-1β and TNF but not CXCL10. Furthermore, paired samples from healthy 1-year-olds collected 1-2 wk apart revealed frequent respiratory virus acquisition or clearance, with mucosal immunophenotype changing in parallel. These findings reveal that frequent, dynamic host-pathogen interactions drive nasal innate immune activation in children.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468425","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}

引用次数: 0

Women in STEM becoming independent: Embrace failures as part of the journey to success. 科技、工程和数学领域的女性变得独立：将失败视为成功之路的一部分。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-31 DOI: 10.1084/jem.20241219

Zhoujie Ding, Nicola Laura Diny, Rebecca Gentek, Shiri Gur-Cohen, Motoko Y Kimura, Hui-Fern Koay, Giuliana Magri, Araceli Perez-Lopez, Natalia Barbara Pikor, Lauren B Rodda

引用次数: 0

B cell tolerance and autoimmunity: Lessons from repertoires. B 细胞耐受性与自身免疫：从复合物中汲取的教训

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-02 DOI: 10.1084/jem.20231314

Jacques Deguine, Ramnik J Xavier

引用次数: 0

A novel STING variant triggers endothelial toxicity and SAVI disease. 一种新型 STING 变体会引发内皮毒性和 SAVI 疾病。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-02 DOI: 10.1084/jem.20232167

Erika Valeri, Sara Breggion, Federica Barzaghi, Monah Abou Alezz, Giovanni Crivicich, Isabel Pagani, Federico Forneris, Claudia Sartirana, Matteo Costantini, Stefania Costi, Achille Marino, Eleonora Chiarotto, Davide Colavito, Rolando Cimaz, Ivan Merelli, Elisa Vicenzi, Alessandro Aiuti, Anna Kajaste-Rudnitski

{"title":"A novel STING variant triggers endothelial toxicity and SAVI disease.","authors":"Erika Valeri, Sara Breggion, Federica Barzaghi, Monah Abou Alezz, Giovanni Crivicich, Isabel Pagani, Federico Forneris, Claudia Sartirana, Matteo Costantini, Stefania Costi, Achille Marino, Eleonora Chiarotto, Davide Colavito, Rolando Cimaz, Ivan Merelli, Elisa Vicenzi, Alessandro Aiuti, Anna Kajaste-Rudnitski","doi":"10.1084/jem.20232167","DOIUrl":"10.1084/jem.20232167","url":null,"abstract":"Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492234","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}

引用次数: 0

The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis. RNA结合蛋白Arid5a驱动IL-17依赖性自身抗体诱导的肾小球肾炎。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-26 DOI: 10.1084/jem.20240656

Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen

{"title":"The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis.","authors":"Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen","doi":"10.1084/jem.20240656","DOIUrl":"10.1084/jem.20240656","url":null,"abstract":"Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759081","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}

引用次数: 0

The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes. 视黄醇核受体信号在癌症和代谢综合征中的致病作用。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-12 DOI: 10.1084/jem.20240519

Mark Esposito, John K Amory, Yibin Kang

{"title":"The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes.","authors":"Mark Esposito, John K Amory, Yibin Kang","doi":"10.1084/jem.20240519","DOIUrl":"10.1084/jem.20240519","url":null,"abstract":"The retinoid nuclear receptor pathway, activated by the vitamin A metabolite retinoic acid, has been extensively investigated for over a century. This study has resulted in conflicting hypotheses about how the pathway regulates health and how it should be pharmaceutically manipulated. These disagreements arise from a fundamental contradiction: retinoid agonists offer clear benefits to select patients with rare bone growth disorders, acute promyelocytic leukemia, and some dermatologic diseases, yet therapeutic retinoid pathway activation frequently causes more harm than good, both through acute metabolic dysregulation and a delayed cancer-promoting effect. In this review, we discuss controlled clinical, mechanistic, and genetic data to suggest several disease settings where inhibition of the retinoid pathway may be a compelling therapeutic strategy, such as solid cancers or metabolic syndromes, and also caution against continued testing of retinoid agonists in cancer patients. Considerable evidence suggests a central role for retinoid regulation of immunity and metabolism, with therapeutic opportunities to antagonize retinoid signaling proposed in cancer, diabetes, and obesity.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916831","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}

引用次数: 0

Dynamic Foxp3-chromatin interaction controls tunable Treg cell function. Foxp3与染色质的动态相互作用控制着可调的Treg细胞功能。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-06-27 DOI: 10.1084/jem.20232068

Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng

{"title":"Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.","authors":"Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng","doi":"10.1084/jem.20232068","DOIUrl":"10.1084/jem.20232068","url":null,"abstract":"Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457370","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}

引用次数: 0

Sarah Gaffen: I thrive on turning my vision for the lab into reality. 莎拉-格芬：我致力于将自己对实验室的设想变为现实。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-19 DOI: 10.1084/jem.20241418

Lucie Van Emmenis

引用次数: 0

Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua. 胎儿 MAVS 和 I 型 IFN 信号通路控制 ZIKV 在胎盘和母体蜕膜中的感染。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-23 DOI: 10.1084/jem.20240694

Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P Muraro, Fang R Zhao, Michelle Elam-Noll, J Michael White, Daiana M Vota, Vanesa C Hauk, Jeffrey I Gordon, Scott A Handley, Michael S Diamond

{"title":"Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua.","authors":"Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P Muraro, Fang R Zhao, Michelle Elam-Noll, J Michael White, Daiana M Vota, Vanesa C Hauk, Jeffrey I Gordon, Scott A Handley, Michael S Diamond","doi":"10.1084/jem.20240694","DOIUrl":"10.1084/jem.20240694","url":null,"abstract":"The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748320","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}

引用次数: 0

Transcription of HIV-1 at sites of intact latent provirus integration. 完整潜伏前病毒整合点的 HIV-1 转录。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-14 DOI: 10.1084/jem.20240391

Ana Rafaela Teixeira, Cintia Bittar, Gabriela S Silva Santos, Thiago Y Oliveira, Amy S Huang, Noemi Linden, Isabella A T M Ferreira, Tetyana Murdza, Frauke Muecksch, R Brad Jones, Marina Caskey, Mila Jankovic, Michel C Nussenzweig

{"title":"Transcription of HIV-1 at sites of intact latent provirus integration.","authors":"Ana Rafaela Teixeira, Cintia Bittar, Gabriela S Silva Santos, Thiago Y Oliveira, Amy S Huang, Noemi Linden, Isabella A T M Ferreira, Tetyana Murdza, Frauke Muecksch, R Brad Jones, Marina Caskey, Mila Jankovic, Michel C Nussenzweig","doi":"10.1084/jem.20240391","DOIUrl":"10.1084/jem.20240391","url":null,"abstract":"HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975773","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}

引用次数: 0