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Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

登革热病抗体依赖性增强机制

基本信息

批准号：
10735317
负责人：
Stylianos Bournazos
金额：
$ 47.71万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735317
关键词：
Affinity Antibodies Antibody Repertoire Antibody-Dependent Enhancement Antigenic Specificity Area Autoimmunity Automobile Driving Biological COVID-19 Cambodia Cellular Assay Clinical Complex Coupled Dengue Dengue Hemorrhagic Fever Dengue Infection Dengue Shock Syndrome Dengue Virus Development Disease Disease susceptibility Event Exhibits Fc domain Funding Heterogeneity High Prevalence Human Immune Immune System Diseases Immune response Immunoglobulin G In Vitro Infection Inflammatory Leukocytes Life Macrophage Macrophage Activation Mediating Memory Modeling Morbidity - disease rate Mothers Mouse Strains Myeloid Cells Newborn Infant Outcome Pathogenesis Pathogenicity Pathway interactions Patients Persons Plasmablast Polysaccharides Population Predisposition Prognostic Factor Public Health Recording of previous events Recurrence Risk Risk Factors Role Serum Severities Severity of illness Spleen Symptoms Therapeutic Transcription Alteration Vaccination Virus Diseases Virus Replication arthropod-borne chemokine cytokine epidemiology study experience immune activation immunological status in vivo in vivo Model infection risk insight mortality mouse model novel pathogenic virus permissiveness receptor response severe dengue targeted treatment transcriptome

项目摘要

ABSTRACT Instead of conferring protection, IgG antibodies against dengue virus (DENV) have been correlated with increased susceptibility to symptomatic dengue disease, as patients with pre-existing antibodies against DENV experience at a higher rate the symptomatic form of dengue disease, which often includes life-threatening complications. With over 2.5 billion people being at risk of DENV infection and with >100 million new infections occurring annually, DENV represents a tremendous burden to global human public health, necessitating the development of efficacious therapeutic or vaccination approaches to control DENV infection and disease. Using in vitro cellular assays, several studies have previously suggested that anti-DENV antibodies can mediate enhanced viral infection of Fcγ receptor (FcγR)-expressing myeloid cells; a phenomenon referred to as antibody dependent enhancement (ADE). However, ADE of viral replication alone cannot account for the complex pathophysiological features of symptomatic dengue disease, as well as for the wide spectrum of clinical disease severity observed among symptomatic patients. During the previous funding period, in collaborative studies with the Institute Pasteur in Cambodia, a DENV endemic area, we demonstrated that dengue disease susceptibility, as well as disease severity are associated with the induction of specific glycoforms of IgG antibodies (afucosylated) that exhibit increased affinity for the activating FcγRIII receptor. In parallel mechanistic studies, we developed a novel in vivo model of dengue disease that expresses the full array of human FcγRs and is permissive for DENV infection. Using this model, we demonstrated that a critical step in the in vivo pathogenesis of dengue disease is the engagement of FcγRIIIa on macrophages by afucosylated IgG antibodies, which are enriched in severe dengue cases. FcγRIIIa-afucosylated IgG antibody interactions result in aberrant macrophage activation, inflammatory sequelae, significant morbidity, and mortality. These findings implicate the FcγRIIIa- afucosylated Fc axis as the basis for dengue disease susceptibility and pathogenesis. Using a unique set of biospecimens from DENV-infected patients, as well as our recently developed mouse models of ADE of dengue disease, the proposed studies aim to (i) dissect the mechanisms that drive the induction of IgG Fc afucosylated glycoforms upon DENV infection and (ii) characterize the downstream effector responses that are initiated upon engagement of FcγRIIIa by afucosylated IgG antibodies and contribute to disease pathogenesis. We anticipate that our findings will significantly advance our understanding of the pathways that regulate IgG Fc glycan heterogeneity during DENV infection and drive dengue disease pathogenesis, having a broader impact on the study of immune responses against other viral pathogens that are characterized by aberrant IgG Fc fucosylation.

摘要针对登革病毒（DENV）的IgG抗体不是赋予保护，而是与以下相关：对症状性登革热的易感性增加，因为患者预先存在DENV抗体有症状的登革热发病率较高，并发症超过25亿人面临DENV感染的风险，新感染人数超过1亿 DENV每年发生一次，对全球人类公共卫生造成巨大负担，开发有效的治疗或疫苗接种方法以控制DENV感染和疾病。使用在体外细胞测定中，一些研究先前已经表明抗DENV抗体可以介导表达Fcγ受体（FcγR）的骨髓细胞的病毒感染增强;这种现象称为抗体依赖性增强（ADE）。然而，单独的病毒复制ADE不能解释复合物症状性登革热病的病理生理学特征，以及广泛的临床疾病在有症状的患者中观察到严重程度。在上一个资助期内，在柬埔寨巴斯德研究所，登革病毒流行区，我们证明了登革疾病易感性，以及疾病的严重程度与IgG抗体的特异性糖型的诱导有关（无岩藻糖基化），其对活化FcγRIII受体表现出增加的亲和力。在平行的机制研究中，我们开发了一种新的登革热病体内模型，该模型表达人Fcγ R的完整阵列，允许DENV感染。使用这个模型，我们证明了体内发病机制中的关键步骤，登革热疾病的最大危险是FcγRIIIa与巨噬细胞上的无岩藻糖基化IgG抗体的结合，在严重的登革热病例中富集。Fcγ RIIIa-无岩藻糖基化IgG抗体相互作用导致异常巨噬细胞活化、炎症后遗症、显著的发病率和死亡率。这些发现表明FcγRIIIa- 无岩藻糖基化Fc轴是登革热病易感性和发病机制的基础。使用一套独特的来自DENV感染患者的生物标本，以及我们最近开发的登革热ADE小鼠模型提出的研究旨在（i）剖析诱导IgG Fc无岩藻糖基化的机制，（ii）表征在DENV感染后启动的下游效应物应答， FcγRIIIa与无岩藻糖基化IgG抗体结合，并促进疾病发病机制。我们预计我们的研究结果将大大促进我们对调节IgG Fc聚糖的途径的理解登革病毒感染过程中的异质性，并驱动登革疾病的发病机制，对登革病毒的感染有更广泛的影响。研究针对以异常IgG Fc岩藻糖基化为特征的其他病毒病原体的免疫应答。