EBioMedicine最新文献

{"title":"Peripheral blood neutrophil proteomic profiling with transcriptomic data integration reveals biomarkers for tuberculosis infection diagnosis.","authors":"Jiarong Yang, Zizheng Lv, Liguo Liu, Han Zhang, Jie Hu, Xingzhu Geng, Henan Xin, Zisen Liu, Lei Gao, Xiaobing Zhang, Yanli Xu, Rongmei Liu, Qi Jin, Jianhua Zheng","doi":"10.1016/j.ebiom.2025.105945","DOIUrl":"10.1016/j.ebiom.2025.105945","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) is one of the deadliest infectious diseases worldwide, causing millions of new cases and deaths annually. Rapid and accurate TB diagnostics are essential for TB control, yet current methods do not fully meet global needs. Peripheral blood neutrophils play a critical role in TB infection and represent a promising source of diagnostic markers.</p><p><strong>Methods: </strong>We conducted a cross-sectional proteomic analysis to characterise neutrophil protein profiles in individuals with active TB (ATB), latent TB infection (LTBI), and healthy controls (HC). Stringent criteria were applied to identify differentially expressed proteins (DEPs) among these groups. Transcriptomic data were integrated to perform pathway enrichment analysis of DEPs. Three DEPs (B2M, TXN, and PRDX5) were further validated as candidate diagnostic biomarkers for Mycobacterium tuberculosis (MTB) infection using automated western blotting in a cohort of 319 individuals, including 71 ATB, 142 LTBI, and 106 HC.</p><p><strong>Findings: </strong>Hundreds of DEPs were identified across the three groups. Integrated transcriptomic analysis revealed significant enrichment of DEPs in the NOD-like receptor signalling pathway. Receiver operating characteristic analysis of the three-protein combination (B2M, TXN, and PRDX5) yielded an area under the curve of 0.9847, with a sensitivity of 95.11% and a specificity of 96.23% for detecting MTB infection.</p><p><strong>Interpretation: </strong>This study presents a comprehensive proteomic profile of neutrophils under different MTB infection states, and this three-protein combination may assist in the diagnosis of MTB infection.</p><p><strong>Funding: </strong>This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-037) and the National Science and Technology Major Project of China (20212017ZX10201301-002-003).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105945"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184952","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}

{"title":"Once-daily dolutegravir/lamivudine fixed-dose formulations in children living with HIV: a pharmacokinetic and safety sub-study nested in the open-label, multicentre, randomised, non-inferiority D3/PENTA 21 trial.","authors":"Lisanne A H Bevers, Gabriela Toledo, Muzamil Kisekka, Elizabeth Kaudha, Grace M Ahimbisibwe, Isabelle Deprez, Tiyara Arumugan, Ebrahim Variava, Avy Violari, Iona White, Dickson Bbuye, Annet Nanduudu, Enoch Mulwanyi, Pauline Amuge, Diana A Rutebarika, Adeodata Kekitiinwa, Cissy Kityo, Philippa Musoke, Moherndran Archary, Justine Boles, Margaret J Thomason, Saskia N de Wildt, Carlo Giaquinto, Angela Colbers, David M Burger, Ann M Buchanan, Man K Chan, Tom G Jacobs, Anna Turkova","doi":"10.1016/j.ebiom.2025.105929","DOIUrl":"10.1016/j.ebiom.2025.105929","url":null,"abstract":"<p><strong>Background: </strong>Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations.</p><p><strong>Methods: </strong>Children aged 2-<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10-<14 kg 4 DTs; 14-<20 kg 5 DTs; 20-<25 kg 6 DTs or 1 FCT; 25-<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG C_trough <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study.</p><p><strong>Findings: </strong>Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9-10.0) years and weight 21.6 (17.7-24.8) kg. DTG geometric mean (GM) (%CV) C_trough and AUC_{0-24 h} were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC_{0-24 h} was 16.2 (45) h∗mg/L. Three children had DTG C_trough<0.32 mg/L, all had DTG C_trough ≥0.064 mg/L. In children weighing 20-<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC_{0-24 h} was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20-<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials.</p><p><strong>Interpretation: </strong>The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use.</p><p><strong>Funding: </strong>The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105929"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181920","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}

{"title":"Poor sleep health is associated with older brain age: the role of systemic inflammation.","authors":"Yuyang Miao, Jiao Wang, Xuerui Li, Jie Guo, Maria M Ekblom, Shireen Sindi, Qiang Zhang, Abigail Dove","doi":"10.1016/j.ebiom.2025.105941","DOIUrl":"10.1016/j.ebiom.2025.105941","url":null,"abstract":"<p><strong>Background: </strong>Poor-quality sleep has been linked to increased dementia risk. We investigated the relationship between healthy sleep pattern and older brain age, and the extent to which this is mediated by systemic inflammation.</p><p><strong>Methods: </strong>The study included 27,500 adults from the UK Biobank (mean age 54.7 y, 54.0% female). The presence of five self-reported healthy sleep characteristics (early chronotype, 7-8 h daily sleep, no insomnia, no snoring, no excessive daytime sleepiness) were summed into a healthy sleep score (0-5 pts) and used to define three sleep patterns: healthy (≥4 pts), intermediate (2-3 pts), and poor (≤1 pt). Low-grade inflammation was estimated using the INFLA-score, a composite index of inflammatory biomarkers. After a mean follow-up of 8.9 y, brain age was estimated using a machine learning model based on 1079 brain MRI phenotypes and used to calculate brain age gap (BAG; i.e., brain age minus chronological age). Data were analysed using linear regression and generalised structural equation models.</p><p><strong>Findings: </strong>At baseline, 898 (3.3%) participants had poor sleep, 15,283 (55.6%) had intermediate sleep, and 11,319 (41.2%) had healthy sleep. Compared to healthy sleep, intermediate (β = 0.25 [0.11, 0.40], P = 0.010) and poor (β = 0.46 [0.05, 0.87], P < 0.001) sleep were associated with significantly higher BAG. In mediation analysis, INFLA-score mediated 6.81% and 10.42% of the associations between intermediate and poor sleep and higher BAG.</p><p><strong>Interpretation: </strong>Poor sleep health may accelerate brain ageing. This may be driven by higher levels of systemic inflammation.</p><p><strong>Funding: </strong>Alzheimerfonden; Demensfonden; Loo and Hans Osterman Foundation for Medical Research; the Knowledge Foundation; Swedish Research Council.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105941"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205981","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":"Seizure detection using wearable electrocardiogram connected to a smartphone: a phase 3 clinical validation study.","authors":"Jesper Jeppesen, Jakob Christensen, Oliver Ahrenfeldt Petersen, Sarah Fenger, Sidsel Armand Larsen, Stephan Wüstenhagen, Stefan Rahr Wagner, Peter Johansen, Sándor Beniczky","doi":"10.1016/j.ebiom.2025.105952","DOIUrl":"10.1016/j.ebiom.2025.105952","url":null,"abstract":"<p><strong>Background: </strong>Automated seizure detection is needed for patient safety and for objective seizure quantification. Wearable seizure detection devices hold great potential to improve patient care. Our objectives were to assess the accuracy of a wearable ECG-device connected to a smartphone, in detecting epileptic seizures in patients with autonomic ictal changes, and evaluate its capability to automatically determine impairment of consciousness.</p><p><strong>Methods: </strong>We conducted a phase 3, prospective, blinded, multicentre, clinical validation study of real-time seizure detection using a predefined algorithm. We recruited consecutive patients admitted to Epilepsy Monitoring Units. Eligible patients experienced seizures with autonomic ictal manifestations, defined as ictal heart rate change exceeding 50 beats per minute, inferred from the first recorded seizure. Patients wore an ECG-device connected to a smartphone. The algorithm, based on heart rate variability, used a personalised detection threshold determined from the first 24 h of recording. During daytime, seizure detection triggered automated behavioural-testing on the smartphone to confirm detection and assess consciousness.</p><p><strong>Findings: </strong>Of 101 enrolled patients, 36 experienced seizures, with 42 seizures recorded from 17 eligible patients. Overall sensitivity across all 42 seizures was 90·5% (95% CI: 77·4-97·3%), median sensitivity per patient was 100% (95% CI: 100-100%). All bilateral tonic-clonic seizures were detected, while sensitivity for other focal seizures was 82·6% (95% CI: 61·2-95·1%), median per patient: 100% (95% CI: 60-100%). Mean false alarm rate was 2·5/day (median per patient: 1·1/day, 95% CI: 0-2·8/day, zero during the night). Device deficiency time was 1·8% and signal loss was 4·5% (median per patient: 0·3% and 0·5% respectively). Use of the behavioural-testing application successfully cancelled all false alarms and accurately identified impairment of consciousness.</p><p><strong>Interpretation: </strong>The wearable ECG device connected to a smartphone accurately detected focal and generalised seizures, and assessed impairment of consciousness.</p><p><strong>Funding: </strong>Independent Research Fund Denmark (grant number 0134-00400B).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105952"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198796","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}

{"title":"DNA methylation mediates the immunosuppressive tumour microenvironment in metastatic endometrial clear cell carcinoma.","authors":"Huiqing Jia, Yang Chen, Guofeng Ma, Sicong Xu, Xiangyan Zhang, Lianpeng Chang, Ping Yang, Yujing Xiao, Xuefeng Xia, Shukun Zhang, Huaxiao Tang, Yilin Mou, Lina Zhang, Haoyan Wang, Jing Bai, Xin Yi, Xiaoming Xing","doi":"10.1016/j.ebiom.2025.105954","DOIUrl":"10.1016/j.ebiom.2025.105954","url":null,"abstract":"<p><strong>Background: </strong>Endometrial clear cell carcinoma (ECCC) is a rare and highly aggressive histological subtype of endometrial cancer with marked metastatic potential. The molecular characteristics and underlying mechanisms governing its metastatic behaviour remain poorly understood. This study aimed to delineate molecular distinctions between metastatic (Pm) and non-metastatic (Pn) primary ECCC tumours, elucidate DNA methylation-mediated regulatory mechanisms driving metastasis, and identify potential epigenetic biomarkers and therapeutic targets.</p><p><strong>Methods: </strong>This multicentre study involved 51 individuals diagnosed with ECCC, leading to the establishment of two independent cohorts: a sequencing cohort (n = 35) for integrated whole-genome methylation and transcriptomic analysis, and a tissue microarray (TMA) cohort (n = 16) to validate key findings.</p><p><strong>Findings: </strong>Tumours exhibiting metastasis were found to possess a profoundly immunosuppressive tumour microenvironment (TME), evidenced by reduced density of tumour-infiltrating lymphocytes (TILs), especially within subsets of anti-tumour immune cells. Further analysis highlighted differential hypermethylation events in Pm tumours that acted as crucial epigenetic switches regulating immune responses. Specifically, methylation at ETS1-binding sites influenced ETS1 regulon activity, thus broadly regulating immune response processes. Epigenetic silencing of key genes in the T cell receptor (TCR) signalling pathway, such as LCK, CD3E, and ZAP70, impaired T cell activation and inhibited the activity of interacting immune pathways. Additionally, we developed a Lasso-derived metastatic risk score model, incorporating TME features (TIL density) and epigenetic predictors (LCK methylation), which demonstrated strong predictive performance (area under the curve [AUC] = 0.859).</p><p><strong>Interpretation: </strong>This study illuminated the \"epigenetic-immune axis\" as a central regulatory mechanism driving ECCC metastasis. DNA methylation systematically silenced immune response genes by targeting ETS1-binding sites and TCR signalling components, thus reconstructing the immunosuppressive TME to facilitate metastasis. The development of the metastatic risk score model and identification of LCK as a potential therapeutic target provide valuable strategies for precision treatment decisions and advancing targeted epigenetic-immune therapies in ECCC.</p><p><strong>Funding: </strong>This work was supported by the National Natural Science Foundation of China, Joint Foundation Programme, Qingdao Municipal Science and Technology Bureau Municipal Science, Shenzhen Science and Technology Programme, and the Affiliated Hospital of Qingdao University Young Investigator Fund.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105954"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12517104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205993","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}

{"title":"TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4⁺ T cell differentiation and interleukin-10 formation.","authors":"Christa Pfeifhofer-Obermair, Natascha Brigo, Chiara Volani, Piotr Tymoszuk, Egon Demetz, Sabine Engl, Günter Weiss","doi":"10.1016/j.ebiom.2025.105910","DOIUrl":"10.1016/j.ebiom.2025.105910","url":null,"abstract":"<p><strong>Background: </strong>Iron loading increases infection risk in being a nutrient for invading siderophilic bacteria and by modulating immune functions including the expression of the immune checkpoint regulator T-cell immunoglobulin-and-mucin-containing-domain-3 (TIM-3). TIM-3 affects specific immune cell functions including T-helper cell differentiation but also T cell dysfunction, and immune exhaustion. Given the prevalence of iron overload specifically in patients at higher risk for infection such as those suffering from hemo-oncological diseases, we investigated TIM-3's role in immune control of bacterial sepsis.</p><p><strong>Methods: </strong>A sepsis model was employed in wildtype and Tim3^-/- mice with transgenic expression of a functional natural resistance associated macrophage protein 1 (NRAMP1). This creates a chronic inflammation model with enhanced resistance to infections with Gram negative Salmonella typhimurium, enabling to study T cell immune responses over time.</p><p><strong>Findings: </strong>Dietary iron supplementation reduced mouse survival, which was further exaggerated by TIM-3 deletion. This indicates that TIM-3 dependent immune regulation was essential for effective host defence against Salmonella. TIM-3 deletion increased the production of immune-deactivating interleukin (IL) -10 as a result of impaired interleukin-12 receptor (IL-12R)-dependent CD4⁺ cytotoxic T cell signalling and development which subsequently reduced the production of anti-microbial interferon gamma (IFNγ). Anti-IL-10 treatment in iron-loaded Tim3^-/- mice improved Salmonella control and restored CD4⁺ T cell mediated IFNγ production.</p><p><strong>Interpretation: </strong>Our study uncovers TIM-3 as a crucial regulator of T cell driven immune control of bacterial infection and identifies the underlying treatable pathways, which is of major importance to better combat infection related mortality in subjects with iron overload syndromes.</p><p><strong>Funding: </strong>Christian-Doppler-Society, FWF (I-3321, W-1253).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105910"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052448","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":"Monocyte/macrophage-derived interleukin-15 mediates the pro-inflammatory phenotype of CD226⁺ B cells in type 1 diabetes.","authors":"Jingyue Li, Xin Liang, Mingjiu Zhao, Wenjun Luo, Juan Huang, Yang Xiao, Jiaqi Huang, Bin Zhao, Zhiguang Zhou","doi":"10.1016/j.ebiom.2025.105946","DOIUrl":"10.1016/j.ebiom.2025.105946","url":null,"abstract":"<p><strong>Background: </strong>Type 1 diabetes (T1D) is characterised by the autoimmune-mediated destruction of pancreatic β-cells. Although traditionally viewed as a disease dominated by T cells, recent studies have emphasised the crucial role of B cells in the development of T1D. Genome-wide association studies (GWAS) have revealed that CD226 is related to susceptibility to several autoimmune diseases, including T1D. Our recent work identified a pathogenic role of CD226⁺ CD8⁺ T cells in T1D. However, the involvement of CD226⁺ B cells in T1D development remains unclear.</p><p><strong>Methods: </strong>The expression and functional characteristics of CD226⁺ B cells in T1D patients and non-obese diabetic (NOD) mice were detected by flow cytometry. RNA sequencing and molecular biology experiments were performed to reveal regulatory mechanisms. In addition, in vivo interventions were conducted to explore potential preventive and therapeutic targets for T1D.</p><p><strong>Findings: </strong>The percentage of CD226⁺ B cells is increased and positively correlated with disease severity in T1D. CD226⁺ B cells from T1D patients and NOD mice exhibit increased capability for activation, proliferation, and production of pro-inflammatory cytokines along with heightened glycolytic metabolism. Mechanistic studies have revealed that interleukin-15 (IL-15) secreted by monocytes or macrophages promotes the inflammatory response of CD226⁺ B cells. Importantly, the use of an anti-CD132 monoclonal antibody (anti-CD132) or an anti-IL-15 monoclonal antibody (anti-IL-15), which blocks IL-15 signalling, effectively prevented the disease onset of T1D. Furthermore, combination therapy with anti-CD3 monoclonal antibody (anti-CD3) and anti-CD132 synergistically reversed hyperglycemia in cyclophosphamide-accelerated NOD mice.</p><p><strong>Interpretation: </strong>Our study demonstrates a novel role of the monocyte/macrophage-IL-15-CD226⁺ B cell axis in T1D immunopathogenesis and provides potential targets for T1D immunotherapy.</p><p><strong>Funding: </strong>This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507300, 2023ZD0507303, 2023ZD0508200, and 2023ZD0508201), the Natural Science Foundation of China (82570973, 82170795, 82470814, 82100949, and 82470931), the Scientific Research Program of FuRong Laboratory (2024PT5105) and the Central South University Research Programme of Advanced Interdisciplinary Studies (2023QYJC008).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105946"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074596","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}

{"title":"IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling.","authors":"Shreya Ghimire, Biyun Xue, Kun Li, Ryan M Gannon, Christine L Wohlford-Lenane, Andrew L Thurman, Huiyu Gong, Grace C Necker, Jian Zheng, David K Meyerholz, Stanley Perlman, Paul B McCray, Alejandro A Pezzulo","doi":"10.1016/j.ebiom.2025.105920","DOIUrl":"10.1016/j.ebiom.2025.105920","url":null,"abstract":"<p><strong>Background: </strong>Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signalling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents.</p><p><strong>Methods: </strong>The role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response was investigated in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo using single-cell and bulk RNA-sequencing approaches. Additionally, the responses were quantified using immunofluorescence, histopathology, immunohistochemistry and LC-MS/MS assays.</p><p><strong>Findings: </strong>IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2-expressing ciliated cells rather than by neutralisation in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened disease severity in mice; the effects were mediated by eicosanoid signalling and were abolished in mice deficient in the phospholipase A₂ enzyme PLA2G2D.</p><p><strong>Interpretation: </strong>IL-13-induced inflammation differentially affects multiple steps of COVID-19 pathogenesis. IL-13-induced inflammation may be protective against initial SARS-CoV-2 airway epithelial infection; however, it enhances disease progression in vivo. Blockade of IL-13 and/or eicosanoid signalling may be protective against progression to severe respiratory virus-induced lung diseases.</p><p><strong>Funding: </strong>Carver Trust COVID-19 Grant; CF Foundation Iowa RDP; NIH 1R01HL163024; K01HL140261; NIH R01AI129269; NIH P01AI060699; NIH Grant P30 DK-54759; Cystic Fibrosis Foundation PEZZUL20A1-KB; Stead Family Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105920"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074683","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}

{"title":"Efficacy of precisely tailored phage cocktails targeting carbapenem-resistant Acinetobacter baumannii reveals evolutionary trade-offs: a proof-of-concept study.","authors":"Ziqiang Liu, Xin Tan, Min Xiong, Shitong Lu, Yongqing Yang, Heng Zhu, Jieqiong Zhang, Xiangying Luo, Caiyun Zhou, Shujiang Wei, Ning Zhou, Xueyan Liu, Changqing Bai, Yongjun Pan, Yingfei Ma","doi":"10.1016/j.ebiom.2025.105942","DOIUrl":"10.1016/j.ebiom.2025.105942","url":null,"abstract":"<p><strong>Background: </strong>The rapid emergence of phage-resistant bacterial mutants and the challenge of developing tailored phage cocktails have significantly hindered the broad application of phage therapy. This is particularly critical for infections caused by highly prevalent strains such as capsule locus 2 (KL2)-type carbapenem-resistant Acinetobacter baumannii (CRAB) in China.</p><p><strong>Methods: </strong>We employed an iterative phage adaptive selection (iPAS) strategy to develop an optimised phage cocktail specifically targeting KL2-type CRAB strains. To facilitate efficient clinical application, we also established a rapid identification method for KL2-type isolates. The efficacy and safety of this rationally designed cocktail were subsequently evaluated in a clinical setting through its application in two compassionate use cases of CRAB infection as a proof-of-concept study. Whole genomic sequencing was conducted on the isolated phage-resistant mutants to reveal the related mutations.</p><p><strong>Findings: </strong>KL2-type A. baumannii was the predominant lineage, accounting for 17.7% (159/896) of isolates reported across China over the past five years, and 33.3% (46/138) of clinical CRAB isolates obtained by our laboratory from five hospitals and one institute in Guangdong Province. The optimised phage cocktail effectively targeted 89.1% (41/46) of these KL2-type isolates. The phage-resistant A. baumannii mutants exhibited beneficial trade-offs, including increased antibiotic sensitivity, reduced virulence, susceptibility to immune clearance, and impaired biofilm formation. Genomic analysis revealed that these trade-offs were driven by concentrated and consistent mutations in genes involved in lipo-oligosaccharide and capsular polysaccharide biosynthesis. Crucially, the application of this cocktail in two clinical cases of CRAB infection demonstrated both clinical efficacy in resolving infections and a favourable safety profile.</p><p><strong>Interpretation: </strong>This research underscores the potential of rational tailored phage cocktails developed through strategies like iPAS, to address the growing threat of CRAB infections. The successful clinical application highlights the translational impact of this study. Furthermore, the study provides valuable insights into the co-evolutionary dynamics between bacteria and phages, paving the way for broader and more effective clinical applications of phage therapy.</p><p><strong>Funding: </strong>This work was supported by National Key R&D Programme of China; Shenzhen Medical Research Funds; Shenzhen Nanshan District Health Technology Major Project; Shenzhen Science and Technology Innovation Commission and Shenzhen Science and Technology Programme.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105942"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091201","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}

{"title":"Authors' reply to letter regarding \"Inflammaging links life's essential 8 to white matter brain aging\".","authors":"Tianzhou Ma, Zhenyao Ye, Li Feng, Shuo Chen","doi":"10.1016/j.ebiom.2025.105909","DOIUrl":"10.1016/j.ebiom.2025.105909","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105909"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063297","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}