Interferon hyperactivity, COVID19, and Down syndrome

干扰素过度活跃、新冠肺炎 (COVID19) 和唐氏综合症

• 批准号: 10215951
• 负责人: Joaquin M. Espinosa
• 金额: $ 61.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215951
• 关键词: 2019-nCoV; Address; Administrative Supplement; Adult Respiratory Distress Syndrome; Affect; Age; Attention; Award; B-Lymphocytes; Bacterial Infections; COVID-19; Cell Lineage; Cells; Cellular Immunity; Characteristics; Chromosome 21; Clinical; Clinical Protocols; Clinical Research; Clinical assessments; Cohort Studies; Collaborations; Custom; Data; Databases; Development; Diagnosis; Diagnostic; Down Syndrome; Electronic Health Record; Ethnic Origin; Exposure to; Funding; Future; Geography; Grant; Human; Humoral Immunities; Hyperactive behavior; Immune; Immunity; Immunologics; Impairment; Incidence; Individual; Infection; Interferon Receptor; Interferons; Investigation; Knowledge; Modality; National Institute of Allergy and Infectious Disease; Parents; Participant; Pathology; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Populations at Risk; Prevention; Preventive; Production; Proteome; RNA; Race; Registries; Research; Research Activity; Research Personnel; Risk; Risk Factors; Sampling; Sepsis; Series; Signal Transduction; Subgroup; Surveys; Survivors; Symptoms; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tube; U-Series Cooperative Agreements; United States National Institutes of Health; Vaccines; Virus; Vulnerable Populations; Work; age difference; biobank; cellular development; cohort; coronavirus disease; cytokine; cytokine release syndrome; genome analysis; high risk; metabolome; microbiome; mouse model; neutralizing antibody; prevent; recruit; response; secondary infection; sex; transcriptome; vaccination strategy

PROJECT SUMMARY. This is an application for an Urgent Competitive Revision to our Transformative R01 award funded by the NIH INCLUDE Project and NIAID titled ‘Understanding Down Syndrome as an Interferonopathy’. The central hypothesis of the parent award is that hyperactivation of interferon (IFN) signaling causes many of the developmental and clinical hallmarks of DS. In this revision, we will investigate the interplay between IFN hyperactivity, immune dysregulation, COVID19 pathology, and immunity against SARS-CoV-2. We hypothesize that IFN hyperactivity will modify the clinical course of COVID19 in DS, including long term immunological sequalae, while potentially impairing development of cellular and humoral immunity against SARS-CoV-2. Our Specific Aims are: 1. Determine the clinical and immunological characteristics of COVID19 in DS. It is increasingly evident that individuals with DS infected by SARS-CoV-2 are more likely to be hospitalized, develop secondary bacterial infections, and die at younger ages. However, many questions remain unanswered about the clinical course of COVID19 in DS. What are the risk factors for severe COVID19 in DS? Are there treatment modalities that are less or more effective in DS? What are the sequalae of SARS-CoV-2 infection in survivors with DS? Here, we will employ the National COVID Cohort Collaborative (N3C), the DS-Connect® registry, and the Human Trisome Project (HTP) cohort study to generate a definitive assessment of the clinical and immunological characteristics of COVID19 in DS. We will complete parallel analyses of the N3C database and data obtained by the HTP team via electronic health record abstraction and participant surveys to identify differences in early symptoms, immunological parameters, clinical course, risk factors, response to different treatment modalities, and long term sequalae, with emphasis on potential differences by age, sex, race/ethnicity, and geography. 2. Investigate the immune phenotype of a cohort of COVID19 survivors with DS. Our extensive investigation of the immune phenotype of people with DS has revealed strong dysregulation of T and B cell lineages, including changes that could impair the development of cellular and humoral immunity against SARS-CoV-2 and the response to SARS-CoV-2 vaccines. Now, supported by the DS-Connect® registry and the HTP cohort study, we will obtain biospecimens from individuals with DS that survived SARS-CoV-2 infection. We will include these samples in our ongoing pan-omics characterization of IFN hyperactivity and immune dysregulation in DS, while also investigating the development and duration of memory T and B cell responses and production of neutralizing antibodies specific for SARS-CoV-2. Altogether, these synergistic aims, which address multiple aspects of this NOSI, will advance our understanding of the impacts of trisomy 21 and IFN hyperactivity on COVID19 in DS, thus informing the rapid development of customized preventive, diagnostics, and therapeutic strategies for this at-risk population.

项目摘要。 这是对由 NIH 资助的变革性 R01 奖项进行紧急竞争性修订的申请 INCLUDE 项目和 NIAID 的标题为“将唐氏综合症理解为干扰素病”。 家长奖的假设是干扰素 (IFN) 信号的过度激活会导致许多 DS 的发育和临床特征 在本次修订中，我们将研究 IFN 之间的相互作用。 多动症、免疫失调、COVID19 病理学和针对 SARS-CoV-2 的免疫力。 IFN 过度活跃将改变 DS 中 COVID19 的临床病程，包括长期免疫学 后遗症，同时可能损害针对 SARS-CoV-2 的细胞和体液免疫的发展。 具体目标是： 1.确定DS中COVID19的临床和免疫学特征。 感染 SARS-CoV-2 的 DS 患者更有可能住院并产生继发细菌 然而，关于该病临床病程的许多问题仍未得到解答。 DS 中的新冠病毒 (COVID19)。 重症 DS 中的新冠病毒 (COVID19) 的危险因素有哪些？ DS 幸存者感染 SARS-CoV-2 后遗症是什么？ 将采用国家新冠肺炎队列协作组织 (N3C)、DS-Connect® 注册中心和人类三体组 项目 (HTP) 队列研究，对临床和免疫学特征进行明确评估 我们将完成 N3C 数据库和 HTP 团队获得的数据的并行分析。 通过电子健康记录提取和参与者调查来识别早期症状的差异， 免疫学参数、临床病程、危险因素、对不同治疗方式的反应以及长期 后遗症，重点是年龄、性别、种族/民族和地理位置的潜在差异。 2. 我们对一群患有 DS 的 COVID19 幸存者的免疫表型进行调查。 DS 患者免疫表型的研究揭示了 T 细胞和 B 细胞谱系的严重失调，包括 可能损害针对 SARS-CoV-2 的细胞和体液免疫发展的变化以及 现在，在 DS-Connect® 注册和 HTP 队列研究的支持下，我们 将从 SARS-CoV-2 感染后幸存的 DS 个体中获取生物样本，我们将包括这些样本。 我们正在进行的 DS 中 IFN 过度活跃和免疫失调的泛组学表征中的样本，同时 还研究了记忆 T 和 B 细胞反应的发展和持续时间以及中和反应的产生 SARS-CoV-2 特异性抗体。 总而言之，这些协同目标解决了 NOSI 的多个方面，将增进我们的理解 21 三体和 IFN 过度活跃对 DS 中的 COVID19 的影响，从而为 DS 的快速发展提供信息 防止针对这一高危人群制定定制的诊断和治疗策略。

项目成果

Tumoural soft tissue calcification in Down syndrome: association with heterozygous germline SAMD9 mutation and hyperactive type I interferon signaling.

唐氏综合症中的肿瘤软组织钙化：与杂合种系 SAMD9 突变和 I 型干扰素信号传导过度活跃相关。

• 发表时间: 2020
• 作者: Deigendesch, Nikolaus;Hirsiger, Julia R;Bigler, Marc B;Ghosh, Adhideb;Harder, Dorothee;Jauch, Annaïse;Espinosa, Joaquin M;Recher, Mike;Navarini, Alexander;Daikeler, Thomas;Berger, Christoph T
• 通讯作者: Berger, Christoph T

Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment.

镰状细胞患者血浆中心肾功能障碍的代谢特征，作为治疗性输血和羟基脲治疗的函数。

• 发表时间: 2023-04-06
• 作者: D'Alessandro, Angelo;Nouraie, S Mehdi;Zhang, Yingze;Cendali, Francesca;Gamboni, Fabia;Reisz, Julie A;Zhang, Xu;Bartsch, Kyle W;Galbraith, Matthew D;Espinosa, Joaquin M;Gordeuk, Victor R;Gladwin, Mark T
• 通讯作者: Gladwin, Mark T

Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling.

干扰素过度活跃通过下调经典 Wnt 信号传导损害唐氏综合症的心脏发生。

• 发表时间: 2023-07-21
• 影响因子: 5.8
• 作者: Chi, Congwu;Knight, Walter E;Riching, Andrew S;Zhang, Zhen;Tatavosian, Roubina;Zhuang, Yonghua;Moldovan, Radu;Rachubinski, Angela L;Gao, Dexiang;Xu, Hongyan;Espinosa, Joaquin M;Song, Kunhua
• 通讯作者: Song, Kunhua

Down Syndrome patients with COVID-19 pneumonia: A high-risk category for unfavourable outcome.

患有 COVID-19 肺炎的唐氏综合症患者：出现不良结果的高风险类别。

• 发表时间: 2021-02
• 作者: Vita, Serena;Di Bari, Virginia;Corpolongo, Angela;Goletti, Delia;Espinosa, Joaquin;Petracca, Sebastiano;Palmieri, Fabrizio;Nicastri, Emanuele;INMI COVID
• 通讯作者: INMI COVID

Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome.

介导激酶抑制可抑制唐氏综合症中过度活跃的干扰素信号传导。

• 发表时间: 2023-12-13
• 作者: Cozzolino, Kira;Sanford, Lynn;Hunter, Samuel;Molison, Kayla;Erickson, Benjamin;Jones, Taylor;Ajit, Deepa;Galbraith, Matthew D;Espinosa, Joaquin M;Bentley, David L;Allen, Mary A;Dowell, Robin D;Taatjes, Dylan J
• 通讯作者: Taatjes, Dylan J