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":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/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}
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":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/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":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/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: 2024-10-03DOI: 10.1016/j.ebiom.2024.105387
Juan Fortea
{"title":"Context matters: the evolving use of biomarkers in Alzheimer's disease care.","authors":"Juan Fortea","doi":"10.1016/j.ebiom.2024.105387","DOIUrl":"10.1016/j.ebiom.2024.105387","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375258","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: 2024-09-27DOI: 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。
{"title":"Ultrapotent class I neutralizing antibodies post Omicron breakthrough infection overcome broad SARS-CoV-2 escape variants.","authors":"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","doi":"10.1016/j.ebiom.2024.105354","DOIUrl":"10.1016/j.ebiom.2024.105354","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Findings: </strong>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 IC<sub>50</sub> 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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.</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/PMC11470419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343703","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}
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.
{"title":"Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenza.","authors":"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","doi":"10.1016/j.ebiom.2024.105343","DOIUrl":"10.1016/j.ebiom.2024.105343","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>A full list of funding sources can be found in the acknowledgements section.</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/PMC11418153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282142","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: 2024-09-14DOI: 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。
{"title":"Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping.","authors":"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","doi":"10.1016/j.ebiom.2024.105328","DOIUrl":"10.1016/j.ebiom.2024.105328","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>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.</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/PMC11419830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282146","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: 2024-09-19DOI: 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.
{"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}
Pub Date : 2024-10-01Epub Date: 2024-09-30DOI: 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).
{"title":"Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice.","authors":"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","doi":"10.1016/j.ebiom.2024.105361","DOIUrl":"10.1016/j.ebiom.2024.105361","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>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).</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/PMC11472634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364802","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}