Pub Date : 2024-10-01Epub Date: 2024-09-27DOI: 10.1016/j.ebiom.2024.105362
Ethan K Gough, Thaddeus J Edens, Lynnea Carr, Ruairi C Robertson, Kuda Mutasa, Robert Ntozini, Bernard Chasekwa, Hyun Min Geum, Iman Baharmand, Sandeep K Gill, Batsirai Mutasa, Mduduzi N N Mbuya, Florence D Majo, Naume Tavengwa, Freddy Francis, Joice Tome, Ceri Evans, Margaret Kosek, Andrew J Prendergast, Amee R Manges
Background: Small-quantity lipid-based nutrient supplements (SQ-LNS), which has been widely tested to reduce child stunting, has largely modest effects to date, but the mechanisms underlying these modest effects are unclear. Child stunting is a longstanding indicator of chronic undernutrition and it remains a prevalent public health problem. The infant gut microbiome may be a key contributor to stunting; and mother and infant fucosyltransferase (FUT) phenotypes are important determinants of infant microbiome composition.
Methods: We investigated whether mother-infant FUT status (n = 792) and infant gut microbiome composition (n = 354 fecal specimens from 172 infants) modified the impact of an infant and young child feeding (IYCF) intervention, that included SQ-LNS, on stunting at age 18 months in secondary analysis of a randomized trial in rural Zimbabwe.
Findings: We found that the impact of the IYCF intervention on stunting was modified by: (i) mother-infant FUT2+/FUT3- phenotype (difference-in-differences -32.6% [95% CI: -55.3%, -9.9%]); (ii) changes in species composition that reflected microbiome maturation (difference-in-differences -68.1% [95% CI: -99.0%, -28.5%); and (iii) greater relative abundance of B. longum (differences-in-differences 49.1% [95% CI: 26.6%, 73.6%]). The dominant strains of B. longum when the intervention started were most similar to the proficient milk oligosaccharide utilizer subspecies infantis, which decreased with infant age and differed by mother-infant FUT2+/FUT3- phenotypes.
Interpretation: These findings indicate that a persistently "younger" microbiome at initiation of the intervention reduced its benefits on stunting in areas with a high prevalence of growth restriction.
Funding: Bill and Melinda Gates Foundation, UK DFID/Aid, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, UNICEF, and Nutricia Research Foundation.
{"title":"Bifidobacterium longum and microbiome maturation modify a nutrient intervention for stunting in Zimbabwean infants.","authors":"Ethan K Gough, Thaddeus J Edens, Lynnea Carr, Ruairi C Robertson, Kuda Mutasa, Robert Ntozini, Bernard Chasekwa, Hyun Min Geum, Iman Baharmand, Sandeep K Gill, Batsirai Mutasa, Mduduzi N N Mbuya, Florence D Majo, Naume Tavengwa, Freddy Francis, Joice Tome, Ceri Evans, Margaret Kosek, Andrew J Prendergast, Amee R Manges","doi":"10.1016/j.ebiom.2024.105362","DOIUrl":"10.1016/j.ebiom.2024.105362","url":null,"abstract":"<p><strong>Background: </strong>Small-quantity lipid-based nutrient supplements (SQ-LNS), which has been widely tested to reduce child stunting, has largely modest effects to date, but the mechanisms underlying these modest effects are unclear. Child stunting is a longstanding indicator of chronic undernutrition and it remains a prevalent public health problem. The infant gut microbiome may be a key contributor to stunting; and mother and infant fucosyltransferase (FUT) phenotypes are important determinants of infant microbiome composition.</p><p><strong>Methods: </strong>We investigated whether mother-infant FUT status (n = 792) and infant gut microbiome composition (n = 354 fecal specimens from 172 infants) modified the impact of an infant and young child feeding (IYCF) intervention, that included SQ-LNS, on stunting at age 18 months in secondary analysis of a randomized trial in rural Zimbabwe.</p><p><strong>Findings: </strong>We found that the impact of the IYCF intervention on stunting was modified by: (i) mother-infant FUT2+/FUT3- phenotype (difference-in-differences -32.6% [95% CI: -55.3%, -9.9%]); (ii) changes in species composition that reflected microbiome maturation (difference-in-differences -68.1% [95% CI: -99.0%, -28.5%); and (iii) greater relative abundance of B. longum (differences-in-differences 49.1% [95% CI: 26.6%, 73.6%]). The dominant strains of B. longum when the intervention started were most similar to the proficient milk oligosaccharide utilizer subspecies infantis, which decreased with infant age and differed by mother-infant FUT2+/FUT3- phenotypes.</p><p><strong>Interpretation: </strong>These findings indicate that a persistently \"younger\" microbiome at initiation of the intervention reduced its benefits on stunting in areas with a high prevalence of growth restriction.</p><p><strong>Funding: </strong>Bill and Melinda Gates Foundation, UK DFID/Aid, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, UNICEF, and Nutricia Research Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105362"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343770","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}
Pub Date : 2024-10-01DOI: 10.1016/j.ebiom.2024.105402
eBioMedicine
{"title":"Hypervirulent Klebsiella pneumoniae: an old enemy with a more powerful weapon.","authors":"eBioMedicine","doi":"10.1016/j.ebiom.2024.105402","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105402","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105402"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406235","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}
Pub Date : 2024-10-01Epub Date: 2024-09-18DOI: 10.1016/j.ebiom.2024.105345
Amanda Cano, María Capdevila, Raquel Puerta, Javier Arranz, Laura Montrreal, Itziar de Rojas, Pablo García-González, Claudia Olivé, Fernando García-Gutiérrez, Oscar Sotolongo-Grau, Adelina Orellana, Nuria Aguilera, Maribel Ramis, Maitee Rosende-Roca, Alberto Lleó, Juan Fortea, Juan Pablo Tartari, Asunción Lafuente, Liliana Vargas, Alba Pérez-Cordón, Nathalia Muñoz, Ángela Sanabria, Montserrat Alegret, Xavier Morató, Lluís Tárraga, Victoria Fernández, Marta Marquié, Sergi Valero, Daniel Alcolea, Mercè Boada, Agustín Ruiz
Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic.
Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181.
Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value.
Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.
Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.
{"title":"Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic.","authors":"Amanda Cano, María Capdevila, Raquel Puerta, Javier Arranz, Laura Montrreal, Itziar de Rojas, Pablo García-González, Claudia Olivé, Fernando García-Gutiérrez, Oscar Sotolongo-Grau, Adelina Orellana, Nuria Aguilera, Maribel Ramis, Maitee Rosende-Roca, Alberto Lleó, Juan Fortea, Juan Pablo Tartari, Asunción Lafuente, Liliana Vargas, Alba Pérez-Cordón, Nathalia Muñoz, Ángela Sanabria, Montserrat Alegret, Xavier Morató, Lluís Tárraga, Victoria Fernández, Marta Marquié, Sergi Valero, Daniel Alcolea, Mercè Boada, Agustín Ruiz","doi":"10.1016/j.ebiom.2024.105345","DOIUrl":"10.1016/j.ebiom.2024.105345","url":null,"abstract":"<p><strong>Background: </strong>The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic.</p><p><strong>Methods: </strong>Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181.</p><p><strong>Findings: </strong>CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value.</p><p><strong>Interpretation: </strong>Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.</p><p><strong>Funding: </strong>This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105345"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282132","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}
Pub Date : 2024-10-01Epub Date: 2024-09-24DOI: 10.1016/j.ebiom.2024.105333
Timothy Bergquist, Johanna Loomba, Emily Pfaff, Fangfang Xia, Zixuan Zhao, Yitan Zhu, Elliot Mitchell, Biplab Bhattacharya, Gaurav Shetty, Tamanna Munia, Grant Delong, Adbul Tariq, Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Seraphina Shi, Rachael V Philips, Andrew Mertens, Romain Pirracchio, Mark van der Laan, John M Colford, Alan Hubbard, Jifan Gao, Guanhua Chen, Neelay Velingker, Ziyang Li, Yinjun Wu, Adam Stein, Jiani Huang, Zongyu Dai, Qi Long, Mayur Naik, John Holmes, Danielle Mowery, Eric Wong, Ravi Parekh, Emily Getzen, Jake Hightower, Jennifer Blase
Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID.
Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.).
Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events.
Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions.
Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.
{"title":"Crowd-sourced machine learning prediction of long COVID using data from the National COVID Cohort Collaborative.","authors":"Timothy Bergquist, Johanna Loomba, Emily Pfaff, Fangfang Xia, Zixuan Zhao, Yitan Zhu, Elliot Mitchell, Biplab Bhattacharya, Gaurav Shetty, Tamanna Munia, Grant Delong, Adbul Tariq, Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Seraphina Shi, Rachael V Philips, Andrew Mertens, Romain Pirracchio, Mark van der Laan, John M Colford, Alan Hubbard, Jifan Gao, Guanhua Chen, Neelay Velingker, Ziyang Li, Yinjun Wu, Adam Stein, Jiani Huang, Zongyu Dai, Qi Long, Mayur Naik, John Holmes, Danielle Mowery, Eric Wong, Ravi Parekh, Emily Getzen, Jake Hightower, Jennifer Blase","doi":"10.1016/j.ebiom.2024.105333","DOIUrl":"10.1016/j.ebiom.2024.105333","url":null,"abstract":"<p><strong>Background: </strong>While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID.</p><p><strong>Methods: </strong>A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.).</p><p><strong>Findings: </strong>Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events.</p><p><strong>Interpretation: </strong>As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions.</p><p><strong>Funding: </strong>Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105333"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343695","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}
Pub Date : 2024-10-01Epub Date: 2024-09-26DOI: 10.1016/j.ebiom.2024.105365
Karlo M Pedro, Mohammed Ali Alvi, Michael G Fehlings
{"title":"Empirical application of a multidimensional approach to capture a broader assessment of clinical benefits in a heterogenous spine population - author's reply.","authors":"Karlo M Pedro, Mohammed Ali Alvi, Michael G Fehlings","doi":"10.1016/j.ebiom.2024.105365","DOIUrl":"10.1016/j.ebiom.2024.105365","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105365"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343696","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}
Pub Date : 2024-10-01Epub Date: 2024-09-04DOI: 10.1016/j.ebiom.2024.105325
Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe
Background: Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.
Methods: Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.
Findings: Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.
Interpretation: These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.
Funding: This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).
背景:肿瘤中神经的轴突生成和神经发生对癌症的发生和发展的影响日益受到关注,癌症神经科学这一新领域正在兴起。最近一项关于前列腺癌的研究表明,肿瘤微环境可能会通过招募表达双皮质素(DCX)的神经祖细胞(NPCs)来影响癌症的进展。方法:在此,我们使用成像质谱细胞计数法研究了患者乳腺癌基质组织中是否存在表达 DCX 的细胞。我们对 107 例乳腺癌组织病理图像中的 372,468 个细胞进行了单细胞分析,从而获得了基质区神经元的空间分辨率以及这些肿瘤的临床病理特征。与此同时,我们建立了一个模拟乳腺癌神经祖细胞神经支配的三维体外模型,并利用基于质谱的全蛋白质组学研究了两种细胞类型在共培养过程中的共同进化:研究结果:在乳腺癌患者的肿瘤组织中,DCX +细胞基质的存在与组织学级别较高的肿瘤、基底样表型和较短的患者生存期有关。全局蛋白质组学分析表明,乳腺癌细胞和神经祖细胞在共培养过程中的蛋白质组结构发生了显著变化:这些结果支持神经参与在乳腺癌中发挥了积极作用,因此有必要进一步研究神经元素与肿瘤进展的相关性:这项工作得到了挪威研究理事会(Research Council of Norway)卓越中心资助计划(项目编号:223250,资助人:L.A.A.)、挪威癌症协会(资助人:L.A.A.和H.V.)、挪威西部地区健康信托基金(Helse Vest)(资助人:L.A.A.)、梅尔泽研究基金(资助人:H.V.)和美国国立卫生研究院(NIH)/美国国立卫生研究院(NIGMS)R01 GM132129基金(资助人:J.A.P.)的支持。
{"title":"Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.","authors":"Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe","doi":"10.1016/j.ebiom.2024.105325","DOIUrl":"10.1016/j.ebiom.2024.105325","url":null,"abstract":"<p><strong>Background: </strong>Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.</p><p><strong>Methods: </strong>Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.</p><p><strong>Findings: </strong>Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.</p><p><strong>Interpretation: </strong>These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.</p><p><strong>Funding: </strong>This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105325"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132156","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}
Pub Date : 2024-10-01Epub Date: 2024-09-18DOI: 10.1016/j.ebiom.2024.105330
Theresa Hautz, Hubert Hackl, Hendrik Gottschling, Raphael Gronauer, Julia Hofmann, Stefan Salcher, Bettina Zelger, Rupert Oberhuber, Benno Cardini, Annemarie Weissenbacher, Thomas Resch, Jakob Troppmair, Stefan Schneeberger
Background: A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters.
Methods: 50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction.
Findings: Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function.
Interpretation: Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation.
Funding: The research was supported by "In Memoriam Dr. Gabriel Salzner Stiftung", Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.
背景:我们需要更好地了解肝脏常温机器灌注(NMP)过程中的分子事件,以开发一种基于数据的方法来鉴定代表移植物质量和移植后预后的生物标志物。我们分析了 NMP 期间的动态转录变化,并将其与临床和生化参数联系起来。在 NMP 前、NMP 期间和再灌注后收集的连续活检组织中进行了大量 RNA 测序。对灌注液进行采样以监测肝功能。对移植肝脏和非移植肝脏、早期同种异体移植功能障碍肝脏和非早期同种异体移植功能障碍肝脏的分子特征进行了比较:研究结果:与免疫和细胞应激反应、细胞贩运和细胞调控有关的通路在 NMP 期间被激活,而细胞代谢则随着时间的推移而下调。抗炎反应和参与组织重塑的基因在较晚的时间点被诱导,这表明了对直接损伤的反作用。NMP 能强烈诱导与缺血再灌注损伤相关的基因特征。7 个基因的特征与 6 h NMP 时移植或丢弃的基准标准一致(曲线下面积为 0.99)。CD274 基因表达(编码程序性细胞死亡配体-1)的预测价值最高。6 h NMP时的LEAP2基因表达与移植物功能受损相关:基因表达标记物的评估可作为评估 NMP 期间肝脏质量的可靠工具,并可预测移植后的早期移植物功能:该研究得到了 "纪念 Gabriel Salzner 博士基金会"、Tiroler Wissenschaftsfond、Jubiläumsfonds-Österreichhe Nationalbank 和 MUI Start 基金的支持。
{"title":"Transcriptomic signatures during normothermic liver machine perfusion correspond with graft quality and predict the early graft function.","authors":"Theresa Hautz, Hubert Hackl, Hendrik Gottschling, Raphael Gronauer, Julia Hofmann, Stefan Salcher, Bettina Zelger, Rupert Oberhuber, Benno Cardini, Annemarie Weissenbacher, Thomas Resch, Jakob Troppmair, Stefan Schneeberger","doi":"10.1016/j.ebiom.2024.105330","DOIUrl":"10.1016/j.ebiom.2024.105330","url":null,"abstract":"<p><strong>Background: </strong>A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters.</p><p><strong>Methods: </strong>50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction.</p><p><strong>Findings: </strong>Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function.</p><p><strong>Interpretation: </strong>Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation.</p><p><strong>Funding: </strong>The research was supported by \"In Memoriam Dr. Gabriel Salzner Stiftung\", Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105330"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282147","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}
Pub Date : 2024-10-01Epub Date: 2024-09-30DOI: 10.1016/j.ebiom.2024.105366
Anastasia K A L Kwee, Eleni-Rosalina Andrinopoulou, Tjeerd van der Veer, Leticia Gallardo-Estrella, Jean-Paul Charbonnier, Stephen M Humphries, David A Lynch, Harm A W M Tiddens, Pim A de Jong, Esther Pompe
Background: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear.
Methods: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume.
Findings: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium.
Interpretation: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers.
Funding: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
{"title":"Higher small pulmonary artery and vein volume on computed tomography is associated with mortality in current and former smokers.","authors":"Anastasia K A L Kwee, Eleni-Rosalina Andrinopoulou, Tjeerd van der Veer, Leticia Gallardo-Estrella, Jean-Paul Charbonnier, Stephen M Humphries, David A Lynch, Harm A W M Tiddens, Pim A de Jong, Esther Pompe","doi":"10.1016/j.ebiom.2024.105366","DOIUrl":"10.1016/j.ebiom.2024.105366","url":null,"abstract":"<p><strong>Background: </strong>In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear.</p><p><strong>Methods: </strong>We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95<sup>th</sup> percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume.</p><p><strong>Findings: </strong>Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m<sup>2</sup> increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium.</p><p><strong>Interpretation: </strong>In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers.</p><p><strong>Funding: </strong>Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105366"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364801","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}
Pub Date : 2024-10-01Epub Date: 2024-09-25DOI: 10.1016/j.ebiom.2024.105363
Can Li, Na Xiao, Wenchen Song, Alvin Hiu-Chung Lam, Feifei Liu, Xinrui Cui, Zhanhong Ye, Yanxia Chen, Peidi Ren, Jianpiao Cai, Andrew Chak-Yiu Lee, Honglin Chen, Zhihua Ou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Hin Chu, Anna Jin-Xia Zhang
Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.
Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.
Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.
Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.
Funding: Funding is listed in the Acknowledgements section.
{"title":"Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters.","authors":"Can Li, Na Xiao, Wenchen Song, Alvin Hiu-Chung Lam, Feifei Liu, Xinrui Cui, Zhanhong Ye, Yanxia Chen, Peidi Ren, Jianpiao Cai, Andrew Chak-Yiu Lee, Honglin Chen, Zhihua Ou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Hin Chu, Anna Jin-Xia Zhang","doi":"10.1016/j.ebiom.2024.105363","DOIUrl":"10.1016/j.ebiom.2024.105363","url":null,"abstract":"<p><strong>Background: </strong>Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.</p><p><strong>Methods: </strong>We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.</p><p><strong>Findings: </strong>We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.</p><p><strong>Interpretation: </strong>Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.</p><p><strong>Funding: </strong>Funding is listed in the Acknowledgements section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105363"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343692","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}
Pub Date : 2024-10-01Epub Date: 2024-09-24DOI: 10.1016/j.ebiom.2024.105342
Zihao Mi, Zhenzhen Wang, Yi Wang, Xiaotong Xue, Xiaojie Liao, Chuan Wang, Lele Sun, Yingjie Lin, Jianwen Wang, Dianhao Guo, Tingting Liu, Jianjun Liu, Robert L Modlin, Hong Liu, Furen Zhang
Background: Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions.
Methods: We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.
Findings: Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8+ T cells, and high RGS1 expression in CD8+ T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG+ CD8+ T cells (CD8+ Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8+ Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.
Interpretation: The state of IL1B macrophages and functional CD8+ T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.
Funding: The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).
{"title":"Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics.","authors":"Zihao Mi, Zhenzhen Wang, Yi Wang, Xiaotong Xue, Xiaojie Liao, Chuan Wang, Lele Sun, Yingjie Lin, Jianwen Wang, Dianhao Guo, Tingting Liu, Jianjun Liu, Robert L Modlin, Hong Liu, Furen Zhang","doi":"10.1016/j.ebiom.2024.105342","DOIUrl":"10.1016/j.ebiom.2024.105342","url":null,"abstract":"<p><strong>Background: </strong>Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions.</p><p><strong>Methods: </strong>We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.</p><p><strong>Findings: </strong>Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8<sup>+</sup> T cells, and high RGS1 expression in CD8<sup>+</sup> T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG<sup>+</sup> CD8<sup>+</sup> T cells (CD8<sup>+</sup> Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8<sup>+</sup> Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.</p><p><strong>Interpretation: </strong>The state of IL1B macrophages and functional CD8<sup>+</sup> T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.</p><p><strong>Funding: </strong>The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105342"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343771","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}