Pub Date : 2024-11-13DOI: 10.1126/scitranslmed.ado2103
Adriana Marques
Protracted fatigue and other symptoms can occur after Lyme disease and other infections, with numerous possible drivers. Studies on posttreatment Lyme disease have been inconclusive, with no confirmed biomarker emerging. Prolonged antibiotic therapy provides no benefit. Thus, a holistic approach toward understanding and treating this complex disease is necessary.
{"title":"Symptoms after Lyme disease: What’s past is prologue","authors":"Adriana Marques","doi":"10.1126/scitranslmed.ado2103","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2103","url":null,"abstract":"Protracted fatigue and other symptoms can occur after Lyme disease and other infections, with numerous possible drivers. Studies on posttreatment Lyme disease have been inconclusive, with no confirmed biomarker emerging. Prolonged antibiotic therapy provides no benefit. Thus, a holistic approach toward understanding and treating this complex disease is necessary.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"189 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601976","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 : 2024-11-13DOI: 10.1126/scitranslmed.ado2106
Annukka A. R. Antar, Andrea L. Cox
Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition.
{"title":"Translating insights into therapies for Long Covid","authors":"Annukka A. R. Antar, Andrea L. Cox","doi":"10.1126/scitranslmed.ado2106","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2106","url":null,"abstract":"Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"35 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601975","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 : 2024-11-13DOI: 10.1126/scitranslmed.ado2099
Sharon H. Saydah, Angela P. Campbell, Adrienne G. Randolph
Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention.
{"title":"Consequences beyond acute SARS-CoV-2 infection in children","authors":"Sharon H. Saydah, Angela P. Campbell, Adrienne G. Randolph","doi":"10.1126/scitranslmed.ado2099","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2099","url":null,"abstract":"Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"158 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601991","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 : 2024-11-13DOI: 10.1126/scitranslmed.adr1032
Rebecca E. Hamlin, Shaun M. Pienkos, Leslie Chan, Mikayla A. Stabile, Kassandra Pinedo, Mallika Rao, Philip Grant, Hector Bonilla, Marisa Holubar, Upinder Singh, Karen B. Jacobson, Prasanna Jagannathan, Yvonne Maldonado, Susan P. Holmes, Aruna Subramanian, Catherine A. Blish
Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST , an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2–like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.
{"title":"Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution","authors":"Rebecca E. Hamlin, Shaun M. Pienkos, Leslie Chan, Mikayla A. Stabile, Kassandra Pinedo, Mallika Rao, Philip Grant, Hector Bonilla, Marisa Holubar, Upinder Singh, Karen B. Jacobson, Prasanna Jagannathan, Yvonne Maldonado, Susan P. Holmes, Aruna Subramanian, Catherine A. Blish","doi":"10.1126/scitranslmed.adr1032","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr1032","url":null,"abstract":"Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced <jats:italic>TGFB1</jats:italic> expression. Females who developed LC demonstrated increased expression of <jats:italic>XIST</jats:italic> , an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced <jats:italic>ETS1</jats:italic> expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that <jats:italic>ETS1</jats:italic> alterations may drive aberrantly elevated T helper cell 2–like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"36 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601973","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 : 2024-11-13DOI: 10.1126/scitranslmed.ado2102
Julio Silva, Akiko Iwasaki
Postacute infection syndromes like Long Covid disproportionately affect females, differing in prevalence, symptoms, and potential causes from males. This Viewpoint highlights these sex differences, gaps in current understanding, and the critical need for sex-based research.
像 Long Covid 这样的急性感染后综合征对女性的影响尤为严重，在发病率、症状和潜在病因方面都与男性不同。本视点强调了这些性别差异、目前认识上的差距以及基于性别进行研究的迫切需要。
{"title":"Sex differences in postacute infection syndromes","authors":"Julio Silva, Akiko Iwasaki","doi":"10.1126/scitranslmed.ado2102","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2102","url":null,"abstract":"Postacute infection syndromes like Long Covid disproportionately affect females, differing in prevalence, symptoms, and potential causes from males. This Viewpoint highlights these sex differences, gaps in current understanding, and the critical need for sex-based research.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"63 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601974","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 : 2024-11-13DOI: 10.1126/scitranslmed.adr9971
Jeanne Marrazzo, Gary H Gibbons, Walter Koroshetz
The NIH's RECOVER Initiative aims to ease the suffering of those living with Long Covid.
美国国立卫生研究院的 "RECOVER 计划 "旨在减轻长颅椎间盘突出症患者的痛苦。
{"title":"Initiating Long Covid RECOVERy.","authors":"Jeanne Marrazzo, Gary H Gibbons, Walter Koroshetz","doi":"10.1126/scitranslmed.adr9971","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr9971","url":null,"abstract":"<p><p>The NIH's RECOVER Initiative aims to ease the suffering of those living with Long Covid.</p>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 773","pages":"eadr9971"},"PeriodicalIF":15.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142626793","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 : 2024-11-06DOI: 10.1126/scitranslmed.adn5449
Luke C. Bartelt, Pawel M. Switonski, Grażyna Adamek, Fabiana Longo, Juliana Carvalho, Lisa A. Duvick, Sabrina I. Jarrah, Hayley S. McLoughlin, Daniel R. Scoles, Stefan M. Pulst, Harry T. Orr, Court Hull, Craig B. Lowe, Albert R. La Spada
Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.
{"title":"Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients","authors":"Luke C. Bartelt, Pawel M. Switonski, Grażyna Adamek, Fabiana Longo, Juliana Carvalho, Lisa A. Duvick, Sabrina I. Jarrah, Hayley S. McLoughlin, Daniel R. Scoles, Stefan M. Pulst, Harry T. Orr, Court Hull, Craig B. Lowe, Albert R. La Spada","doi":"10.1126/scitranslmed.adn5449","DOIUrl":"10.1126/scitranslmed.adn5449","url":null,"abstract":"<div >Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588533","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 : 2024-11-06DOI: 10.1126/scitranslmed.adn0396
Christopher D. Petro, Andrea T. Hooper, Avery Peace, Kusha Mohammadi, Will Eagan, Sayda M. Elbashir, Anthony DiPiazza, Daniel Makrinos, Kristen Pascal, Pooja Bandawane, Mauricio Durand, Ranu Basu, Alida Coppi, Bei Wang, Jacquelynn Golubov, Seblewongel Asrat, Samit Ganguly, Ellen-Marie Koehler-Stec, Matthew F. Wipperman, George Ehrlich, Ana M. Gonzalez Ortiz, Flonza Isa, Mark G. Lewis, Hanne Andersen, Bret J. Musser, Marcela Torres, Wen-Yi Lee, Darin Edwards, Dimitris Skokos, Jamie Orengo, Matthew Sleeman, Thomas Norton, Meagan O’Brien, Eduardo Forleo-Neto, Gary A. Herman, Jennifer D. Hamilton, Andrew J. Murphy, Christos A. Kyratsous, Alina Baum
Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein–directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti–spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2–infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.
由于越来越多地使用抗病毒单克隆抗体（mAbs）进行治疗和预防，因此有必要更好地了解它们对疫苗和病毒内源性免疫的影响。严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）大流行为研究接受抗病毒 mAbs 并随后接种了编码 mAb 靶向病毒尖抗原疫苗的个体的免疫力提供了机会。在这里，我们描述了在人类、非人灵长类动物和小鼠体内施用卡西利韦单抗加伊莫德单抗（CAS+IMD）的抗体组合对随后接种 SARS-CoV-2 疫苗的免疫反应的影响。接种疫苗时使用 CAS+IMD 会导致疫苗诱导的伪病毒中和抗体滴度下降，但不会全面抑制尖峰蛋白导向的免疫反应，包括抗体、B 细胞和 T 细胞反应。对伪病毒中和抗体滴度的影响还延伸到了其他治疗性抗尖峰蛋白抗体的单一疗法或联合疗法。伪病毒中和滴度的特定降低是表位掩蔽的结果，即特定表位被高亲和力抗体结合并阻止 B 细胞识别的现象。令人鼓舞的是，假病毒中和滴度的降低在额外接种加强疫苗后是可逆的。此外，通过评估接受 CAS+IMD 治疗的 SARS-CoV-2 感染者的抗病毒免疫反应，我们发现接受过 mAb 治疗的感染者的抗病毒体液免疫发生了变化，但这种变化只发生在接受 mAb 治疗时尚未开始启动自然免疫反应的感染者身上。这些数据共同证明，抗病毒 mAb 可在疫苗接种或感染过程中改变内源性体液免疫。
{"title":"Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection","authors":"Christopher D. Petro, Andrea T. Hooper, Avery Peace, Kusha Mohammadi, Will Eagan, Sayda M. Elbashir, Anthony DiPiazza, Daniel Makrinos, Kristen Pascal, Pooja Bandawane, Mauricio Durand, Ranu Basu, Alida Coppi, Bei Wang, Jacquelynn Golubov, Seblewongel Asrat, Samit Ganguly, Ellen-Marie Koehler-Stec, Matthew F. Wipperman, George Ehrlich, Ana M. Gonzalez Ortiz, Flonza Isa, Mark G. Lewis, Hanne Andersen, Bret J. Musser, Marcela Torres, Wen-Yi Lee, Darin Edwards, Dimitris Skokos, Jamie Orengo, Matthew Sleeman, Thomas Norton, Meagan O’Brien, Eduardo Forleo-Neto, Gary A. Herman, Jennifer D. Hamilton, Andrew J. Murphy, Christos A. Kyratsous, Alina Baum","doi":"10.1126/scitranslmed.adn0396","DOIUrl":"10.1126/scitranslmed.adn0396","url":null,"abstract":"<div >Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein–directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti–spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2–infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588797","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 : 2024-11-06DOI: 10.1126/scitranslmed.adh9940
Jingjing Ding, Huaizheng Liu, Xiaoxun Zhang, Nan Zhao, Ying Peng, Junping Shi, Jinjun Chen, Xiaoling Chi, Ling Li, Mengni Zhang, Wen-Yue Liu, Liangjun Zhang, Jiafeng Ouyang, Qian Yuan, Min Liao, Ya Tan, Mingqiao Li, Ziqian Xu, Wan Tang, Chuanming Xie, Yi Li, Qiong Pan, Ying Xu, Shi-Ying Cai, Christopher D. Byrne, Giovanni Targher, Xinshou Ouyang, Liqun Zhang, Zhongyong Jiang, Ming-Hua Zheng, Fengjun Sun, Jin Chai
Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.
{"title":"Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population","authors":"Jingjing Ding, Huaizheng Liu, Xiaoxun Zhang, Nan Zhao, Ying Peng, Junping Shi, Jinjun Chen, Xiaoling Chi, Ling Li, Mengni Zhang, Wen-Yue Liu, Liangjun Zhang, Jiafeng Ouyang, Qian Yuan, Min Liao, Ya Tan, Mingqiao Li, Ziqian Xu, Wan Tang, Chuanming Xie, Yi Li, Qiong Pan, Ying Xu, Shi-Ying Cai, Christopher D. Byrne, Giovanni Targher, Xinshou Ouyang, Liqun Zhang, Zhongyong Jiang, Ming-Hua Zheng, Fengjun Sun, Jin Chai","doi":"10.1126/scitranslmed.adh9940","DOIUrl":"10.1126/scitranslmed.adh9940","url":null,"abstract":"<div >Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588798","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 : 2024-11-06DOI: 10.1126/scitranslmed.adq1789
Benjamin R. Babcock, Astrid Kosters, Devon J. Eddins, Maria Sophia Baluyot Donaire, Sannidhi Sarvadhavabhatla, Vivian Pae, Fiona Beltran, Victoria W. Murray, Gurjot Gill, Guorui Xie, Brian S. Dobosh, Vincent D. Giacalone, Rabindra M. Tirouvanziam, Richard P. Ramonell, Scott A. Jenks, Ignacio Sanz, F. Eun-Hyung Lee, Nadia R. Roan, Sulggi A. Lee, Eliver E. B. Ghosn
Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.
{"title":"Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19","authors":"Benjamin R. Babcock, Astrid Kosters, Devon J. Eddins, Maria Sophia Baluyot Donaire, Sannidhi Sarvadhavabhatla, Vivian Pae, Fiona Beltran, Victoria W. Murray, Gurjot Gill, Guorui Xie, Brian S. Dobosh, Vincent D. Giacalone, Rabindra M. Tirouvanziam, Richard P. Ramonell, Scott A. Jenks, Ignacio Sanz, F. Eun-Hyung Lee, Nadia R. Roan, Sulggi A. Lee, Eliver E. B. Ghosn","doi":"10.1126/scitranslmed.adq1789","DOIUrl":"10.1126/scitranslmed.adq1789","url":null,"abstract":"<div >Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588499","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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