Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.adk0845
Sebastian Ochoa, Amy P. Hsu, Andrew J. Oler, Dhaneshwar Kumar, Daniel Chauss, Jan Piet van Hamburg, Gustaaf G. van Laar, Vasileios Oikonomou, Sundar Ganesan, Elise M. N. Ferré, Monica M. Schmitt, Tom DiMaggio, Princess Barber, Gregory M. Constantine, Lindsey B. Rosen, Paul G. Auwaerter, Bhumika Gandhi, Jennifer L. Miller, Rachel Eisenberg, Arye Rubinstein, Edith Schussler, Erjola Balliu, Vandana Shashi, Olaf Neth, Peter Olbrich, Kim My Le, Nanni Mamia, Saila Laakso, Pasi I. Nevalainen, Juha Grönholm, Mikko R. J. Seppänen, Louis Boon, Gulbu Uzel, Luis M. Franco, Theo Heller, Karen K. Winer, Rajarshi Ghosh, Bryce A. Seifert, Magdalena Walkiewicz, Luigi D. Notarangelo, Qing Zhou, Ivona Askentijevich, William Gahl, Cliffton L. Dalgard, Lalith Perera, Behdad Afzali, Sander W. Tas, Steven M. Holland, Michail S. Lionakis
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE–expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.
{"title":"A deep intronic splice–altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion","authors":"Sebastian Ochoa, Amy P. Hsu, Andrew J. Oler, Dhaneshwar Kumar, Daniel Chauss, Jan Piet van Hamburg, Gustaaf G. van Laar, Vasileios Oikonomou, Sundar Ganesan, Elise M. N. Ferré, Monica M. Schmitt, Tom DiMaggio, Princess Barber, Gregory M. Constantine, Lindsey B. Rosen, Paul G. Auwaerter, Bhumika Gandhi, Jennifer L. Miller, Rachel Eisenberg, Arye Rubinstein, Edith Schussler, Erjola Balliu, Vandana Shashi, Olaf Neth, Peter Olbrich, Kim My Le, Nanni Mamia, Saila Laakso, Pasi I. Nevalainen, Juha Grönholm, Mikko R. J. Seppänen, Louis Boon, Gulbu Uzel, Luis M. Franco, Theo Heller, Karen K. Winer, Rajarshi Ghosh, Bryce A. Seifert, Magdalena Walkiewicz, Luigi D. Notarangelo, Qing Zhou, Ivona Askentijevich, William Gahl, Cliffton L. Dalgard, Lalith Perera, Behdad Afzali, Sander W. Tas, Steven M. Holland, Michail S. Lionakis","doi":"10.1126/scitranslmed.adk0845","DOIUrl":"10.1126/scitranslmed.adk0845","url":null,"abstract":"<div >Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (<i>AIRE</i>) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic <i>AIRE</i> variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic <i>AIRE</i> variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of <i>AIRE</i>-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level <i>AIRE</i> expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic <i>AIRE</i>–expressing cell lines. Through protein modeling and transcriptomic analyses of <i>AIRE</i>-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal <i>AIRE</i> transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing <i>AIRE</i> variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245149","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 : 2024-09-18DOI: 10.1126/scitranslmed.adn4970
Zin Z. Khaing, Jannik Leyendecker, Jennifer N. Harmon, Sananthan Sivakanthan, Lindsay N. Cates, Jeffrey E. Hyde, Melissa Krueger, Robb W. Glenny, Matthew Bruce, Christoph P. Hofstetter
Traumatic spinal cord injury (tSCI) causes an immediate loss of neurological function, and the prediction of recovery is difficult in the acute phase. In this study, we used contrast-enhanced ultrasound imaging to quantify intraspinal vascular disruption acutely after tSCI. In a rodent thoracic tSCI model, contrast-enhanced ultrasound revealed a perfusion area deficit that was positively correlated with injury severity and negatively correlated with hindlimb locomotor function at 8 weeks after injury. The spinal perfusion index was calculated by normalizing the contrast inflow at the injury center to the contrast inflow in the injury periphery. The spinal perfusion index decreased with increasing injury severity and positively correlated with hindlimb locomotor function at 8 weeks after injury. The feasibility of intraoperative contrast-enhanced ultrasound imaging was further tested in a cohort of 27 patients with acute tSCI of varying severity and including both motor-complete and motor-incomplete tSCIs. Both the perfusion area deficit and spinal perfusion index were different between motor-complete and motor-incomplete patients. Moreover, the perfusion area deficit and spinal perfusion index correlated with the injury severity at intake and exhibited a correlation with extent of functional recovery at 6 months. Our data suggest that intraoperative contrast-enhanced, ultrasound-derived metrics are correlated with injury severity and chronic functional outcome after tSCI. Larger clinical studies are required to better assess the reliability of the proposed contrast-enhanced ultrasound biomarkers and their prognostic capacity.
{"title":"Perfusion imaging metrics after acute traumatic spinal cord injury are associated with injury severity in rats and humans","authors":"Zin Z. Khaing, Jannik Leyendecker, Jennifer N. Harmon, Sananthan Sivakanthan, Lindsay N. Cates, Jeffrey E. Hyde, Melissa Krueger, Robb W. Glenny, Matthew Bruce, Christoph P. Hofstetter","doi":"10.1126/scitranslmed.adn4970","DOIUrl":"10.1126/scitranslmed.adn4970","url":null,"abstract":"<div >Traumatic spinal cord injury (tSCI) causes an immediate loss of neurological function, and the prediction of recovery is difficult in the acute phase. In this study, we used contrast-enhanced ultrasound imaging to quantify intraspinal vascular disruption acutely after tSCI. In a rodent thoracic tSCI model, contrast-enhanced ultrasound revealed a perfusion area deficit that was positively correlated with injury severity and negatively correlated with hindlimb locomotor function at 8 weeks after injury. The spinal perfusion index was calculated by normalizing the contrast inflow at the injury center to the contrast inflow in the injury periphery. The spinal perfusion index decreased with increasing injury severity and positively correlated with hindlimb locomotor function at 8 weeks after injury. The feasibility of intraoperative contrast-enhanced ultrasound imaging was further tested in a cohort of 27 patients with acute tSCI of varying severity and including both motor-complete and motor-incomplete tSCIs. Both the perfusion area deficit and spinal perfusion index were different between motor-complete and motor-incomplete patients. Moreover, the perfusion area deficit and spinal perfusion index correlated with the injury severity at intake and exhibited a correlation with extent of functional recovery at 6 months. Our data suggest that intraoperative contrast-enhanced, ultrasound-derived metrics are correlated with injury severity and chronic functional outcome after tSCI. Larger clinical studies are required to better assess the reliability of the proposed contrast-enhanced ultrasound biomarkers and their prognostic capacity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245166","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 : 2024-09-18DOI: 10.1126/scitranslmed.ado7189
Roeland Vanhauwaert, Julien Oury, Bernhardt Vankerckhoven, Christophe Steyaert, Stine Marie Jensen, Dana L. E. Vergoossen, Christa Kneip, Leah Santana, Jamie L. Lim, Jaap J. Plomp, Roy Augustinus, Shohei Koide, Christophe Blanchetot, Peter Ulrichts, Maartje G. Huijbers, Karen Silence, Steven J. Burden
Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.
{"title":"ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome","authors":"Roeland Vanhauwaert, Julien Oury, Bernhardt Vankerckhoven, Christophe Steyaert, Stine Marie Jensen, Dana L. E. Vergoossen, Christa Kneip, Leah Santana, Jamie L. Lim, Jaap J. Plomp, Roy Augustinus, Shohei Koide, Christophe Blanchetot, Peter Ulrichts, Maartje G. Huijbers, Karen Silence, Steven J. Burden","doi":"10.1126/scitranslmed.ado7189","DOIUrl":"10.1126/scitranslmed.ado7189","url":null,"abstract":"<div >Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of <i>DOK7</i> CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult <i>Dok7</i> CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado7189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245155","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 : 2024-09-18DOI: 10.1126/scitranslmed.adk7832
Anushka Saha, Trirupa Chakraborty, Javad Rahimikollu, Hanxi Xiao, Lorena B. Pereira de Oliveira, Timothy W. Hand, Sukwan Handali, W. Evan Secor, Lucia A. O. Fraga, Jessica K. Fairley, Jishnu Das, Aniruddh Sarkar
Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.
{"title":"Deep humoral profiling coupled to interpretable machine learning unveils diagnostic markers and pathophysiology of schistosomiasis","authors":"Anushka Saha, Trirupa Chakraborty, Javad Rahimikollu, Hanxi Xiao, Lorena B. Pereira de Oliveira, Timothy W. Hand, Sukwan Handali, W. Evan Secor, Lucia A. O. Fraga, Jessica K. Fairley, Jishnu Das, Aniruddh Sarkar","doi":"10.1126/scitranslmed.adk7832","DOIUrl":"10.1126/scitranslmed.adk7832","url":null,"abstract":"<div >Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245167","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 : 2024-09-18DOI: 10.1126/scitranslmed.adl1997
Benoît Manfroi, Bui Thi Cuc, Aurélien Sokal, Alexis Vandenberghe, Sarah Temmam, Mikaël Attia, Mohamed El Behi, Francesco Camaglia, Ngan Thu Nguyen, Jelka Pohar, Layale Salem-Wehbe, Valentine Pottez-Jouatte, Sibyline Borzakian, Narcisse Elenga, Caroline Galeotti, Guillaume Morelle, Camille de truchis de Lays, Michaela Semeraro, Anne-Sophie Romain, Mélodie Aubart, Naim Ouldali, Florence Mahuteau-Betzer, Claire Beauvineau, Elsa Amouyal, Romain Berthaud, Célia Crétolle, Marc Duval Arnould, Albert Faye, Mathie Lorrot, Grégoire Benoist, Nelly Briand, Marie Courbebaisse, Roland Martin, Peter Van Endert, Jean-Sébastien Hulot, Anne Blanchard, Eric Tartour, Maria Leite-de-Moraes, Guillaume Lezmi, Mickael Ménager, Marine Luka, Claude-Agnès Reynaud, Jean-Claude Weill, Laetitia Languille, Marc Michel, Pascal Chappert, Thierry Mora, Aleksandra M. Walczak, Marc Eloit, Petra Bacher, Alexander Scheffold, Matthieu Mahévas, Isabelle Sermet-Gaudelus, Simon Fillatreau
The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–reactive CD3+CD4+CD154+ T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4+ T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4+ T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2–reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner.
人类免疫系统的发育在出生后持续数年。这一成熟阶段对适应性免疫质量和幼年感染后获得免疫记忆的影响仍未完全明确。在这里，我们使用抗原反应性 T 细胞（ARTE）检测法和多维流式细胞术分析了感染前、感染期间和感染后 11 个月儿童和成人中循环的严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）反应性 CD3+CD4+CD154+ T 细胞，并根据疾病严重程度将儿童和成人分为不同的年龄组。在感染 SARS-CoV-2 期间，5 岁以下儿童的 CD4+ T 细胞抗病毒反应较低，而 5 岁以上儿童和轻症成人的 CD4+ T 细胞对病毒的反应在数量和表型上具有可比性。重症成人的反应特点是病毒反应性促炎性和细胞毒性 T 细胞的频率较高。学龄前儿童在感染 SARS-CoV-2 后，不仅能维持与成人相当的中和 SARS-CoV-2 反应抗体，而且记忆 T 细胞的表型也与成人不同，具有高度炎症特征和向炎症部位迁移的特性。此外，与其他组群相比，学龄前儿童的循环病毒反应记忆 B 细胞明显较少。总之，我们的研究结果揭示了人类幼年抗病毒免疫的独特面貌，并表明针对 SARS-CoV-2 的适应性反应的成熟是以渐进的方式进行的，其特征与成人相似。
{"title":"Preschool-age children maintain a distinct memory CD4+ T cell and memory B cell response after SARS-CoV-2 infection","authors":"Benoît Manfroi, Bui Thi Cuc, Aurélien Sokal, Alexis Vandenberghe, Sarah Temmam, Mikaël Attia, Mohamed El Behi, Francesco Camaglia, Ngan Thu Nguyen, Jelka Pohar, Layale Salem-Wehbe, Valentine Pottez-Jouatte, Sibyline Borzakian, Narcisse Elenga, Caroline Galeotti, Guillaume Morelle, Camille de truchis de Lays, Michaela Semeraro, Anne-Sophie Romain, Mélodie Aubart, Naim Ouldali, Florence Mahuteau-Betzer, Claire Beauvineau, Elsa Amouyal, Romain Berthaud, Célia Crétolle, Marc Duval Arnould, Albert Faye, Mathie Lorrot, Grégoire Benoist, Nelly Briand, Marie Courbebaisse, Roland Martin, Peter Van Endert, Jean-Sébastien Hulot, Anne Blanchard, Eric Tartour, Maria Leite-de-Moraes, Guillaume Lezmi, Mickael Ménager, Marine Luka, Claude-Agnès Reynaud, Jean-Claude Weill, Laetitia Languille, Marc Michel, Pascal Chappert, Thierry Mora, Aleksandra M. Walczak, Marc Eloit, Petra Bacher, Alexander Scheffold, Matthieu Mahévas, Isabelle Sermet-Gaudelus, Simon Fillatreau","doi":"10.1126/scitranslmed.adl1997","DOIUrl":"10.1126/scitranslmed.adl1997","url":null,"abstract":"<div >The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–reactive CD3<sup>+</sup>CD4<sup>+</sup>CD154<sup>+</sup> T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4<sup>+</sup> T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4<sup>+</sup> T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2–reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245170","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}
Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
{"title":"Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging","authors":"Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte","doi":"10.1126/scitranslmed.adg1777","DOIUrl":"10.1126/scitranslmed.adg1777","url":null,"abstract":"<div >Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of <i>octamer-binding transcription factor 4</i> (<i>Oct4</i>), <i>sex-determining region Y-box 2</i> (<i>Sox2</i>), <i>Kruppel-like factor 4</i> (<i>Klf4</i>), and <i>cellular myelocytomatosis oncogene</i> (<i>cMyc</i>) (<i>OSKM</i>) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring <i>OSK</i> under the control of the <i>cyclin-dependent kinase inhibitor 2a</i> (<i>Cdkn2a</i>) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific <i>OSK</i> expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying <i>Cdkn2a-OSK</i> to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying <i>Cdkn2a</i>-<i><i>OSK</i></i> led to improved wound healing in aged wild-type mice. Expression of <i>CDKN2A</i>-<i>OSK</i> in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170434","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 : 2024-09-11DOI: 10.1126/scitranslmed.ads5741
{"title":"Erratum for the Research Article “Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70” by B. Brook et al.","authors":"","doi":"10.1126/scitranslmed.ads5741","DOIUrl":"10.1126/scitranslmed.ads5741","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170414","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 : 2024-09-11DOI: 10.1126/scitranslmed.ado4463
Alice Dejoux, Qianqian Zhu, Christelle Ganneau, Odile Richard-Le Goff, Ophélie Godon, Julien Lemaitre, Francis Relouzat, François Huetz, Aurélien Sokal, Alexis Vandenberghe, Cyprien Pecalvel, Lise Hunault, Thomas Derenne, Caitlin M. Gillis, Bruno Iannascoli, Yidan Wang, Thierry Rose, Christel Mertens, Pascale Nicaise-Roland, NASA Study Group, Patrick England, Matthieu Mahévas, Luc de Chaisemartin, Roger Le Grand, Hélène Letscher, Frederick Saul, Cédric Pissis, Ahmed Haouz, Laurent L. Reber, Pascal Chappert, Friederike Jönsson, Didier G. Ebo, Gaël A. Millot, Sylvie Bay, Sylvie Chollet-Martin, Aurélie Gouel-Chéron, Pierre Bruhns
Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.
{"title":"Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models","authors":"Alice Dejoux, Qianqian Zhu, Christelle Ganneau, Odile Richard-Le Goff, Ophélie Godon, Julien Lemaitre, Francis Relouzat, François Huetz, Aurélien Sokal, Alexis Vandenberghe, Cyprien Pecalvel, Lise Hunault, Thomas Derenne, Caitlin M. Gillis, Bruno Iannascoli, Yidan Wang, Thierry Rose, Christel Mertens, Pascale Nicaise-Roland, NASA Study Group, Patrick England, Matthieu Mahévas, Luc de Chaisemartin, Roger Le Grand, Hélène Letscher, Frederick Saul, Cédric Pissis, Ahmed Haouz, Laurent L. Reber, Pascal Chappert, Friederike Jönsson, Didier G. Ebo, Gaël A. Millot, Sylvie Bay, Sylvie Chollet-Martin, Aurélie Gouel-Chéron, Pierre Bruhns","doi":"10.1126/scitranslmed.ado4463","DOIUrl":"10.1126/scitranslmed.ado4463","url":null,"abstract":"<div >Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170415","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 : 2024-09-11DOI: 10.1126/scitranslmed.adp0004
Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P. Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N. Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L. Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Abhinav K. Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J. Shpall, Ken Chen, Hussein A. Abbas, Kunal Rai, Katayoun Rezvani, May Daher
Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.
骨髓增生异常综合征和急性髓性白血病（AML）属于髓系恶性肿瘤的一种连续性疾病谱，在复发/难治的情况下预后较差，需要采用新型疗法。髓系恶性肿瘤患者的自然杀伤（NK）细胞表现出整体功能障碍，杀伤能力受损，新陈代谢改变，在单细胞转录组和蛋白质组水平上表现出衰竭表型。在这项研究中，我们发现这种功能障碍是通过 NK 细胞和髓样细胞之间的交叉对话介导的，而这种交叉对话需要细胞与细胞之间的接触。NK细胞功能障碍可通过靶向αvβ-整合素/TGF-β/SMAD通路来预防，但一旦形成，就会因深刻的表观遗传重编程而持续存在。我们发现 BATF 是一种核心转录因子，也是导致 AML 中 NK 细胞功能障碍的主要介质。从机理上讲，我们发现BATF直接受SMAD2/3调控和诱导，进而与NK细胞衰竭相关的关键基因结合，如HAVCR2、LAG3、TIGIT和CTLA4。删除 BATF 可增强 NK 细胞在体外和体内抗 AML 的功能。总之，我们的研究结果揭示了一种之前未被发现的NK免疫在AML中的逃避机制，这种机制表现为NK细胞的表观遗传重排和髓细胞瘤的失活。这项工作强调了使用健康的异体NK细胞作为治疗髓系恶性肿瘤患者的采纳性细胞疗法的重要性，同时还强调了通过靶向TGF-β途径或BATF来预防功能障碍的策略的重要性。
{"title":"BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML","authors":"Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P. Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N. Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L. Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Abhinav K. Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J. Shpall, Ken Chen, Hussein A. Abbas, Kunal Rai, Katayoun Rezvani, May Daher","doi":"10.1126/scitranslmed.adp0004","DOIUrl":"10.1126/scitranslmed.adp0004","url":null,"abstract":"<div >Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as <i>HAVCR2</i>, <i>LAG3</i>, <i>TIGIT</i>, and <i>CTLA4</i>. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170426","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 : 2024-09-11DOI: 10.1126/scitranslmed.adk9149
João Da Silva Filho, Vanessa Herder, Matthew P. Gibbins, Monique Freire dos Reis, Gisely Cardoso Melo, Michael J. Haley, Carla Cristina Judice, Fernando Fonseca Almeida Val, Mayla Borba, Tatyana Almeida Tavella, Vanderson de Sousa Sampaio, Charalampos Attipa, Fiona McMonagle, Derek Wright, Marcus Vinicius Guimaraes de Lacerda, Fabio Trindade Maranhão Costa, Kevin N. Couper, Wuelton Marcelo Monteiro, Luiz Carlos de Lima Ferreira, Christopher Alan Moxon, Massimo Palmarini, Matthias Marti
COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: “early death” (<15 days until death) and “late death” (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2+ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2+ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (TH17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, TH2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.
{"title":"A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories","authors":"João Da Silva Filho, Vanessa Herder, Matthew P. Gibbins, Monique Freire dos Reis, Gisely Cardoso Melo, Michael J. Haley, Carla Cristina Judice, Fernando Fonseca Almeida Val, Mayla Borba, Tatyana Almeida Tavella, Vanderson de Sousa Sampaio, Charalampos Attipa, Fiona McMonagle, Derek Wright, Marcus Vinicius Guimaraes de Lacerda, Fabio Trindade Maranhão Costa, Kevin N. Couper, Wuelton Marcelo Monteiro, Luiz Carlos de Lima Ferreira, Christopher Alan Moxon, Massimo Palmarini, Matthias Marti","doi":"10.1126/scitranslmed.adk9149","DOIUrl":"10.1126/scitranslmed.adk9149","url":null,"abstract":"<div >COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: “early death” (<15 days until death) and “late death” (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2<sup>+</sup> macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2<sup>+</sup> epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (T<sub>H</sub>17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, T<sub>H</sub>2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170408","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}
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