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Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics. 单细胞多模态全息研究揭示麻风肉芽肿中细菌负担的细胞和分子决定因素。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-24 DOI: 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).

背景:目前尚不清楚哪些细胞群决定着感染性肉芽肿中细菌的命运。麻风病是一种由麻风分枝杆菌感染引起的肉芽肿性疾病,具有很强的遗传倾向,表现出细菌负荷不同的独特亚型,被认为是研究宿主-病原体相互作用的杰出疾病模型:我们对 11 名健康对照组和 20 名麻风病患者进行了单细胞 RNA 和免疫复合物测序,并将单细胞数据与麻风病全基因组遗传数据进行了整合。我们还进行了多重免疫组化、体外和体内感染实验,以证实多模态全息研究结果:结果:具有高细菌负荷的麻风肉芽肿(L-LEP)的特点是CD8+ T细胞衰竭,CD8+ T细胞中RGS1的高表达与L-LEP有关。与此相反,细菌负荷低的结核性麻风(T-LEP)肉芽肿则富集了具有高 GNLY 表达的常驻记忆 IFNG+ CD8+ T 细胞(CD8+ Trm)。这种富集可能归因于 IL1B 巨噬细胞和 CD8+ Trm 之间通过 CXCL10-CXCR3 信号的交流。此外,L-LEP 中的 IL1B 巨噬细胞表现出抗炎表型,高 APOE 表达导致高细菌负荷。相反,T-LEP 中的 IL1B 巨噬细胞则因干扰素-γ 诱导的 GBP 家族基因而与众不同:IL1B巨噬细胞和功能性CD8+ T细胞的状态以及它们之间的关系对于控制肉芽肿内细菌的持续存在至关重要。这些发现可能为分枝杆菌和其他细胞内细菌引起的肉芽肿疾病的宿主定向免疫疗法指明了潜在的靶点:山东省重点研发计划(2021LCZX07)、山东省自然科学基金(ZR2023MH046)、山东第一医科大学(山东省医学科学院)青年科学基金项目(202201-123)、国家自然科学基金(82471800、82230107、82273545、82304039)、中国博士后科学基金(2023M742162)、山东省泰山学者项目(tspd20230608)、山东省临床与基础研究联合创新团队(202410)、中央引导地方科技发展项目(YDZX2023058)。
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引用次数: 0
Higher small pulmonary artery and vein volume on computed tomography is associated with mortality in current and former smokers. 计算机断层扫描显示的肺小动脉和小静脉容量较高与当前和过去吸烟者的死亡率有关。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-30 DOI: 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.

背景:在慢性阻塞性肺病(COPD)中,血管改变已被证明是导致缺氧和肺动脉高压的原因之一,但小血管异常对死亡率的独立影响仍不清楚:我们对计算机断层扫描(CT)上的动脉和静脉尺寸进行了量化,最小可达 0.2 毫米。374名从不吸烟者的小血管体积(小动脉和小静脉的百分位数)分为两组:正常组和高小动脉或小静脉体积组。我们描述了小动脉和小静脉容量大的受试者的临床、生理和成像特征:研究结果:小动脉和小静脉容量高与死亡率有独立关联,调整后的危险比分别为每 mL/m2 增加 1.07 [1.01, 1.14] 和 1.34 [1.21, 1.49]。在 COPDGene 中,447 例(5.7%)受试者的小动脉容积偏高,519 例(9.1%)受试者的小静脉容积偏高,两者都有更多的肺气肿、更多的空气潴留和更严重的冠状动脉钙化:解释:在吸烟者中,小动脉和小静脉的异常高容量都与死亡率有关,因此需要对吸烟者肺部小血管和心脏功能的病因进行研究:获奖编号:U01-HL089897 和 U01-HL089856,由美国国家健康与生物研究所(NHLBI)颁发。COPD 基金会,阿斯利康、勃林格殷格翰、基因泰克、葛兰素史克、诺华、辉瑞、西门子和 Sunovion 提供捐款。
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引用次数: 0
Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters. 慢性肺部炎症和CK14+基底细胞增殖诱导SARS-CoV-2感染仓鼠肺泡支气管持续扩张
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-25 DOI: 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.

背景:COVID-19急性后遗症是指在感染SARS-CoV-2后很长一段时间内持续出现的一系列症状和病症,包括呼吸系统疾病。肺部组织病理学变化及其内在机制仍难以捉摸:我们研究了感染 SARS-CoV-2 的雄性仓鼠在 7、14、42、84 和 120dpi 的肺组织病理学和转录变化,并与甲型 H1N1 pdm09 感染进行了比较:我们发现,SARS-CoV-2 而非 H1N1 感染后,肺部出现病毒残留、炎症和纤维化变化。从 42dpi 到 120dpi 期间,每只感染了 SARS-CoV-2 的仓鼠(31/31)都出现了最显著的组织病理学病变,即多灶肺泡支气管化。增殖的(Ki67+)CK14+基底细胞在7dpi时聚集在支气管附近的肺泡中,它们在那里增殖并分化成SCGB1A+俱乐部细胞或Tubulin+纤毛细胞,形成肺泡-支气管化病灶。分子上,Notch通路在42和120dpi时明显上调,在肺泡-支气管化病灶中Notch3和Hes1蛋白密集表达,表明Notch信号转导参与了肺泡-支气管化的持续。空间转录组分析进一步证明了这一点。耐人寻味的是,一些促进细胞生长的通路和基因(如 Tubb4b、Stxbp4、Grb14 和 Mlf1)的显著上调与支气管化病变在空间上重叠:解读:肺部 SARS-CoV-2 感染未完全清除,病毒残留、慢性炎症和纤维化损伤以及肺泡支气管化损害了呼吸功能。在组织再生过程中,CK14+基底细胞的异常激活导致持续的 Notch 信号传导导致肺泡支气管化。这项研究加深了我们对呼吸道PASC的理解,为疾病管理提供了启示,并强调了监测呼吸道PASC患者疾病进展的必要性:经费来源见致谢部分。
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引用次数: 0
Context matters: the evolving use of biomarkers in Alzheimer's disease care. 背景很重要:生物标志物在阿尔茨海默病护理中的应用不断发展。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-10-03 DOI: 10.1016/j.ebiom.2024.105387
Juan Fortea
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引用次数: 0
Ultrapotent class I neutralizing antibodies post Omicron breakthrough infection overcome broad SARS-CoV-2 escape variants. Omicron 突破性感染后的超强 I 类中和抗体克服了广泛的 SARS-CoV-2 逃逸变体。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-27 DOI: 10.1016/j.ebiom.2024.105354
Mengxiao Luo, Runhong Zhou, Bingjie Tang, Hang Liu, Bohao Chen, Na Liu, Yufei Mo, Pengfei Zhang, Ye Lim Lee, Jonathan Daniel Ip, Allen Wing-Ho Chu, Wan-Mui Chan, Hiu-On Man, Yuting Chen, Kelvin Kai-Wang To, Kwok-Yung Yuen, Shangyu Dang, Zhiwei Chen

Background: The spread of emerging SARS-CoV-2 immune escape sublineages, especially JN.1 and KP.2, has resulted in new waves of COVID-19 globally. The evolving memory B cell responses elicited by the parental Omicron variants to subvariants with substantial antigenic drift remain incompletely investigated.

Methods: Using the single B cell antibody cloning technology, we isolated single memory B cells, delineated the B cell receptor repertoire and conducted the pseudovirus-based assay for recovered neutralizing antibodies (NAb) screening. We analyzed the cryo-EM structures of top broadly NAbs (bnAbs) and evaluated their in vivo efficacy (golden Syrian hamster model).

Findings: By investigating the evolution of human B cell immunity, we discovered a new panel of bnAbs arising from vaccinees after Omicron BA.2/BA.5 breakthrough infections. Two lead bnAbs neutralized major Omicron subvariants including JN.1 and KP.2 with IC50 values less than 10 ng/mL, representing ultrapotent receptor binding domain (RBD)-specific class I bnAbs. They belonged to the IGHV3-53/3-66 clonotypes instead of evolving from the pre-existing vaccine-induced IGHV1-58/IGKV3-20 bnAb ZCB11. Despite sequence diversity, they targeted previously unrecognized, highly conserved conformational epitopes in the receptor binding motif (RBM) for ultrapotent ACE2 blockade. The lead bnAb ZCP3B4 not only protected the lungs of hamsters intranasally challenged with BA.5.2, BQ.1.1 and XBB.1.5 but also prevented their contact transmission.

Interpretation: Our findings demonstrated that class I bnAbs have evolved an ultrapotent mode of action protecting against highly transmissible and broad Omicron escape variants, and their epitopes are potential targets for novel bnAbs and vaccine development.

Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

背景:新出现的SARS-CoV-2免疫逃逸亚系(尤其是JN.1和KP.2)的传播导致全球范围内出现新一轮的COVID-19。亲代 Omicron 变体对具有大量抗原漂移的亚变体所引起的不断演变的记忆 B 细胞反应仍未得到充分研究:方法:我们利用单个 B 细胞抗体克隆技术分离了单个记忆 B 细胞,划分了 B 细胞受体谱系,并进行了基于假病毒的恢复性中和抗体(NAb)筛选试验。我们分析了顶级广谱中和抗体(bnAbs)的冷冻电镜结构,并评估了它们的体内疗效(金色叙利亚仓鼠模型):通过研究人类B细胞免疫的进化过程,我们发现了一组新的bnAbs,这些bnAbs来自于Omicron BA.2/BA.5突破性感染后的疫苗接种者。两种先导bnAbs中和了包括JN.1和KP.2在内的主要奥米克龙亚变体,其IC50值小于10纳克/毫升,代表了超能受体结合域(RBD)特异性I类bnAbs。它们属于 IGHV3-53/3-66 克隆型,而不是从先前存在的疫苗诱导的 IGHV1-58/IGKV3-20 bnAb ZCB11 演化而来。尽管序列存在多样性,但它们针对的是受体结合基序(RBM)中以前未识别的、高度保守的构象表位,可实现超强 ACE2 阻断。主要的 bnAb ZCP3B4 不仅能保护经鼻内感染 BA.5.2、BQ.1.1 和 XBB.1.5 的仓鼠的肺部,还能阻止它们的接触传播:我们的研究结果表明,I类bnAbs已进化出一种超强的作用模式,可保护高度传播和广泛的奥米克龙逃逸变体,其表位是新型bnAbs和疫苗开发的潜在靶点:本研究的全部资助机构名单见致谢部分。
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引用次数: 0
Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenza. TOMM34 对 COVID-19 和流感重症患者中与 NF-κB 激活相关的高炎症反应的作用
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-13 DOI: 10.1016/j.ebiom.2024.105343
Qiwen Shi, Pengfei Zhang, Qingtao Hu, Tianxin Zhang, Ruixia Hou, Shengxiang Yin, Yilin Zou, Fenghua Chen, Shuang Jiao, Lanlan Si, Bangjin Zheng, Yichao Chen, Tingzhu Zhan, Yongxiang Liu, Wenting Zhu, Nan Qi

Background: Highly pathogenic respiratory RNA viruses such as SARS-CoV-2 and its associated syndrome COVID-19 pose a tremendous threat to the global public health. Innate immune responses to SARS-CoV-2 depend mainly upon the NF-κB-mediated inflammation. Identifying unknown host factors driving the NF-κB activation and inflammation is crucial for the development of immune intervention strategies.

Methods: Published single-cell RNA sequencing (scRNA-seq) data was used to analyze the differential transcriptome profiles of bronchoalveolar lavage (BAL) cells between healthy individuals (n = 27) and patients with severe COVID-19 (n = 21), as well as the differential transcriptome profiles of peripheral blood mononuclear cells (PBMCs) between healthy individuals (n = 22) and severely ill patients with COVID-19 (n = 45) or influenza (n = 16). Loss-of-function and gain-of-function assays were performed in diverse viruses-infected cells and male mice models to identify the role of TOMM34 in antiviral innate immunity.

Findings: TOMM34, together with a list of genes encoding pro-inflammatory cytokines and antiviral immune proteins, was transcriptionally upregulated in circulating monocytes, lung epithelium and innate immune cells from individuals with severe COVID-19 or influenza. Deficiency of TOMM34/Tomm34 significantly impaired the type I interferon responses and NF-κB-mediated inflammation in various human/murine cell lines, murine bone marrow-derived macrophages (BMDMs) and in vivo. Mechanistically, TOMM34 recruits TRAF6 to facilitate the K63-linked polyubiquitination of NEMO upon viral infection, thus promoting the downstream NF-κB activation.

Interpretation: In this study, viral induction of TOMM34 is positively correlated with the hyperinflammation in severely ill patients with COVID-19 and influenza. Our findings also highlight the physiological role of TOMM34 in the innate antiviral signallings.

Funding: A full list of funding sources can be found in the acknowledgements section.

背景:高致病性呼吸道 RNA 病毒(如 SARS-CoV-2 及其相关综合征 COVID-19)对全球公共卫生构成了巨大威胁。对 SARS-CoV-2 的先天免疫反应主要依赖于 NF-κB 介导的炎症反应。确定驱动 NF-κB 激活和炎症的未知宿主因子对于制定免疫干预策略至关重要:方法:利用已发表的单细胞 RNA 测序(scRNA-seq)数据分析了健康人(n = 27)与 COVID-19 重症患者(n = 21)之间支气管肺泡灌洗液(BAL)细胞的差异转录组图谱,以及健康人(n = 22)与 COVID-19 重症患者(n = 45)或流感患者(n = 16)之间外周血单核细胞(PBMCs)的差异转录组图谱。在多种病毒感染细胞和雄性小鼠模型中进行了功能缺失和功能获得试验,以确定 TOMM34 在抗病毒先天免疫中的作用:TOMM34与一系列编码促炎细胞因子和抗病毒免疫蛋白的基因一起,在严重COVID-19或流感患者的循环单核细胞、肺上皮细胞和先天免疫细胞中转录上调。在各种人/鼠细胞系、鼠骨髓源性巨噬细胞(BMDMs)和体内,TOMM34/Tomm34的缺失会显著削弱I型干扰素反应和NF-κB介导的炎症反应。从机理上讲,TOMM34 在病毒感染时会招募 TRAF6 以促进与 K63 链接的 NEMO 多泛素化,从而促进下游 NF-κB 的激活:在这项研究中,病毒诱导的TOMM34与COVID-19和流感重症患者的炎症反应呈正相关。我们的研究结果还强调了TOMM34在先天性抗病毒信号中的生理作用:资金来源的完整列表请参见致谢部分。
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引用次数: 0
Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping. 光学基因组图谱揭示的组织特异性 TCF4 三重节重复不稳定性
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-14 DOI: 10.1016/j.ebiom.2024.105328
Christina Zarouchlioti, Stephanie Efthymiou, Stefano Facchini, Natalia Dominik, Nihar Bhattacharyya, Siyin Liu, Marcos Abreu Costa, Anita Szabo, Amanda N Sadan, Albert S Jun, Enrico Bugiardini, Henry Houlden, Andrea Cortese, Pavlina Skalicka, Lubica Dudakova, Kirithika Muthusamy, Michael E Cheetham, Alison J Hardcastle, Petra Liskova, Stephen J Tuft, Alice E Davidson

Background: Fuchs endothelial corneal dystrophy (FECD) is the most common repeat-mediated disease in humans. It exclusively affects corneal endothelial cells (CECs), with ≤81% of cases associated with an intronic TCF4 triplet repeat (CTG18.1). Here, we utilise optical genome mapping (OGM) to investigate CTG18.1 tissue-specific instability to gain mechanistic insights.

Methods: We applied OGM to a diverse range of genomic DNAs (gDNAs) from patients with FECD and controls (n = 43); CECs, leukocytes and fibroblasts. A bioinformatics pipeline was developed to robustly interrogate CTG18.1-spanning DNA molecules. All results were compared with conventional polymerase chain reaction-based fragment analysis.

Findings: Analysis of bio-samples revealed that expanded CTG18.1 alleles behave dynamically, regardless of cell-type origin. However, clusters of CTG18.1 molecules, encompassing ∼1800-11,900 repeats, were exclusively detected in diseased CECs from expansion-positive cases. Additionally, both progenitor allele size and age were found to influence the level of leukocyte-specific CTG18.1 instability.

Interpretation: OGM is a powerful tool for analysing somatic instability of repeat loci and reveals here the extreme levels of CTG18.1 instability occurring within diseased CECs underpinning FECD pathophysiology, opening up new therapeutic avenues for FECD. Furthermore, these findings highlight the broader translational utility of FECD as a model for developing therapeutic strategies for rarer diseases similarly attributed to somatically unstable repeats.

Funding: UK Research and Innovation, Moorfields Eye Charity, Fight for Sight, Medical Research Council, NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Grantová Agentura České Republiky, Univerzita Karlova v Praze, the National Brain Appeal's Innovation Fund and Rosetrees Trust.

背景:富克斯内皮性角膜营养不良症(FECD)是人类最常见的重复介导疾病。它只影响角膜内皮细胞(CECs),≤81%的病例与内含子TCF4三重重复(CTG18.1)有关。在此,我们利用光学基因组图谱(OGM)研究 CTG18.1 的组织特异性不稳定性,以获得机理上的见解:我们将 OGM 应用于来自 FECD 患者和对照组(n = 43)、CECs、白细胞和成纤维细胞的各种基因组 DNA(gDNAs)。我们开发了一个生物信息学管道,用于对跨越 CTG18.1 的 DNA 分子进行稳健的检测。所有结果都与传统的基于聚合酶链反应的片段分析进行了比较:对生物样本的分析表明,无论细胞类型来源如何,CTG18.1等位基因的扩增都是动态的。然而,CTG18.1分子群(包括1800-11900个重复序列)只在扩增阳性病例的病变CEC中被检测到。此外,祖细胞等位基因的大小和年龄都会影响白细胞特异性 CTG18.1 的不稳定性水平:OGM是分析重复位点体细胞不稳定性的强大工具,它揭示了CTG18.1在病变CEC中的极端不稳定性水平,是FECD病理生理学的基础,为FECD开辟了新的治疗途径。此外,这些研究结果还强调了FECD作为一种模型的更广泛的转化用途,可用于为类似的体细胞不稳定重复序列导致的罕见疾病制定治疗策略:英国研究与创新协会、Moorfields Eye Charity、Fight for Sight、医学研究委员会、Moorfields Eye Hospital 和 UCL 眼科研究所的 NIHR BRC、Grantová Agentura České Republiky、Univerzita Karlova v Praze、National Brain Appeal's Innovation Fund 和 Rosetrees Trust。
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引用次数: 0
Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation. 治疗性单细胞景观:甲氨蝶呤在全身炎症下损害肺泡上皮细胞的干性,从而加剧间质性肺病。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.ebiom.2024.105339
Sung Hae Chang, Seyoung Jung, Jeong Jun Chae, Jeong Yeon Kim, Seon Uk Kim, Ji Yong Choi, Hye-Jeong Han, Hyun Taek Kim, Hak-Jae Kim, Hyun Je Kim, Woong Yang Park, Jeffrey A Sparks, Eun Young Lee, Jeong Seok Lee

Background: Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial.

Methods: Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD.

Findings: Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment.

Interpretation: These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor.

Funding: This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.

背景:间质性肺病(ILD)对类风湿性关节炎(RA)患者构成严重威胁。然而,包括甲氨蝶呤(MTX)和 TNF 抑制剂在内的基础药物对 RA 相关 ILD(RA-ILD)的影响仍存在争议:我们利用SKG小鼠模型和单细胞转录组学研究了MTX和TNF阻断剂对ILD的影响:我们的研究发现,MTX 可通过促进免疫细胞浸润、Th17 激活和纤维化来加重肺部炎症。相反,TNF 抑制剂可改善这些特征并抑制 ILD 的发展。对人类RA-ILD队列数据的分析表明,ILD进展患者的全身炎症持续高于未进展患者,尤其是在接受MTX治疗的亚组中:鉴于MTX和TNF抑制剂的治疗结果不同,这些发现凸显了RA-ILD个性化治疗方法的必要性:本研究由GENINUS公司、韩国国家研究基金会和首尔国立大学医院资助。
{"title":"Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation.","authors":"Sung Hae Chang, Seyoung Jung, Jeong Jun Chae, Jeong Yeon Kim, Seon Uk Kim, Ji Yong Choi, Hye-Jeong Han, Hyun Taek Kim, Hak-Jae Kim, Hyun Je Kim, Woong Yang Park, Jeffrey A Sparks, Eun Young Lee, Jeong Seok Lee","doi":"10.1016/j.ebiom.2024.105339","DOIUrl":"10.1016/j.ebiom.2024.105339","url":null,"abstract":"<p><strong>Background: </strong>Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial.</p><p><strong>Methods: </strong>Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD.</p><p><strong>Findings: </strong>Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment.</p><p><strong>Interpretation: </strong>These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor.</p><p><strong>Funding: </strong>This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282145","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
Reply to: Editorial "The increasing use of T-cell stimulation for successful dengue vaccination" in eBioMedicine 2024; 102, 105120. DOI: https://doi.org/10.1016/j.ebiom.2024.105120. 回复:eBioMedicine 2024; 102, 105120 上的社论 "越来越多地使用 T 细胞刺激成功接种登革热疫苗"。DOI: https://doi.org/10.1016/j.ebiom.2024.105120.
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-28 DOI: 10.1016/j.ebiom.2024.105370
Walid Kandeil, Eduardo Nascimento, Vianney Tricou, Mayuri Sharma, Derek Wallace
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引用次数: 0
Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice. Th1与Th2免疫偏向对SARS-CoV-2变异感染人ACE2基因敲入小鼠病毒、病理和免疫动态的影响
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-30 DOI: 10.1016/j.ebiom.2024.105361
Shailendra Kumar Verma, Fernanda Ana-Sosa-Batiz, Julia Timis, Norazizah Shafee, Erin Maule, Paolla Beatriz Almeida Pinto, Chris Conner, Kristen M Valentine, Dale O Cowley, Robyn Miller, Annie Elong Ngono, Linda Tran, Krithik Varghese, Rúbens Prince Dos Santos Alves, Kathryn M Hastie, Erica Ollmann Saphire, David R Webb, Kurt Jarnagin, Kenneth Kim, Sujan Shresta

Background: Mouse models that recapitulate key features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are important tools for understanding complex interactions between host genetics, immune responses, and SARS-CoV-2 pathogenesis. Little is known about how predominantly cellular (Th1 type) versus humoral (Th2 type) immune responses influence SARS-CoV-2 dynamics, including infectivity and disease course.

Methods: We generated knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) on Th1-biased (C57BL/6; B6) and Th2-biased (BALB/c) genetic backgrounds. Mice were infected intranasally with SARS-CoV-2 Delta (B.1.617.2) or Omicron BA.1 (B.1.1.529) variants, followed by assessment of disease course, respiratory tract infection, lung histopathology, and humoral and cellular immune responses.

Findings: In both B6 and BALB/c mice, hACE2 expression was required for infection of the lungs with Delta, but not Omicron BA.1. Disease severity was greater in Omicron BA.1-infected hTMPRSS2-KI and double-KI BALB/c mice compared with B6 mice, and in Delta-infected double-KI B6 and BALB/c mice compared with hACE2-KI mice. hACE2-KI B6 mice developed more severe lung pathology and more robust SARS-CoV-2-specific splenic CD8 T cell responses compared with hACE2-KI BALB/c mice. There were no notable differences between the two genetic backgrounds in plasma cell, germinal center B cell, or antibody responses to SARS-CoV-2.

Interpretation: SARS-CoV-2 Delta and Omicron BA.1 infection, disease course, and CD8 T cell response are influenced by the host genetic background. These humanized mice hold promise as important tools for investigating the mechanisms underlying the heterogeneity of SARS-CoV-2-induced pathogenesis and immune response.

Funding: This work was funded by NIH U19 AI142790-02S1, the GHR Foundation, the Arvin Gottleib Foundation, and the Overton family (to SS and EOS); Prebys Foundation (to SS); NIH R44 AI157900 (to KJ); and by an American Association of Immunologists Career Reentry Fellowship (FASB).

背景:再现严重急性呼吸系统综合征冠状病毒-2(SARS-CoV-2)感染关键特征的小鼠模型是了解宿主遗传学、免疫反应和 SARS-CoV-2 发病机制之间复杂相互作用的重要工具。关于细胞免疫反应(Th1 型)与体液免疫反应(Th2 型)如何影响 SARS-CoV-2 的动态变化,包括感染性和病程,目前所知甚少:方法:我们在 Th1 型(C57BL/6;B6)和 Th2 型(BALB/c)遗传背景上培育了表达人 ACE2(hACE2)和/或人 TMPRSS2(hTMPRSS2)的基因敲入(KI)小鼠。小鼠经鼻内感染 SARS-CoV-2 Delta(B.1.617.2)或 Omicron BA.1 (B.1.1.529)变体,然后评估病程、呼吸道感染、肺组织病理学以及体液和细胞免疫反应:在 B6 和 BALB/c 小鼠中,肺部感染 Delta 需要 hACE2 的表达,而感染 Omicron BA.1 则不需要。与 B6 小鼠相比,感染 Omicron BA.1 的 hTMPRSS2-KI 和双 KI BALB/c 小鼠的疾病严重程度更高;与 hACE2-KI 小鼠相比,感染 Delta 的双 KI B6 和 BALB/c 小鼠的疾病严重程度更高。与 hACE2-KI BALB/c 小鼠相比,hACE2-KI B6 小鼠的肺部病变更严重,脾脏 CD8 T 细胞特异性反应更强。两种遗传背景的小鼠在浆细胞、生殖中心 B 细胞或抗体对 SARS-CoV-2 的反应方面没有明显差异:解释:SARS-CoV-2 Delta 和 Omicron BA.1 的感染、病程和 CD8 T 细胞反应受宿主遗传背景的影响。这些人源化小鼠有望成为研究 SARS-CoV-2 诱导的发病机制和免疫反应异质性的重要工具:本研究由美国国立卫生研究院 U19 AI142790-02S1、GHR 基金会、Arvin Gottleib 基金会和 Overton 家族(资助 SS 和 EOS);Prebys 基金会(资助 SS);美国国立卫生研究院 R44 AI157900(资助 KJ);以及美国免疫学家协会 Career Reentry Fellowship(FASB)资助。
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引用次数: 0
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EBioMedicine
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