Altered peptide ligands and immunopathogenesis of dengue virus infection

改变的肽配体和登革热病毒感染的免疫发病机制

基本信息

批准号：
7588956
负责人：
Allison Anne Imrie
金额：
$ 20.72万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588956
关键词：
Amino Acid Sequence Antigens Autologous Avidity Biological Assay CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular Immunity Classification Complex Consensus Coupled Cross-Sectional Studies Data Dengue Dengue Hemorrhagic Fever Dengue Shock Syndrome Dengue Virus Disease Epidemic Epidemiology Epitopes Fever Frequencies Future Genes Hawaii Human Immune response Immunity Individual Infection Inflammatory Interferon Type II Interferons Lead Ligands Lymphocytic choriomeningitis virus Measures Mediating Memory Morbidity - disease rate Pacific Island Americans Pathogenesis Peptides Phenotype Population Principal Investigator Production Publishing RNA-Directed RNA Polymerase Research Research Project Grants Role Safety Serotyping Severity of illness Staining method Stains Synthetic Peptide Libraries System T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes TNF gene Techniques Testing Tumor Necrosis Factor-alpha Vaccine Design Vaccines Variant Vascular Endothelium Viral Viral Genome Virus Virus Diseases Work base cross reactivity cytokine human TNF protein improved memory recall mortality programs response secondary infection vaccine development

项目摘要

Principal Investigator/Program Director (Last, first, middle): Imrie, Allison 1 R21 AI074831-01A2 Dengue causes significant morbidity and mortality in tropical and subtropical regions, where it is endemic. Infection with any of the 4 dengue viruses may be asymptomatic or may lead to a self-limiting febrile illness known as dengue fever. A small proportion of dengue fever cases progress to dengue hemorrhagic fever (DHF), or to the most severe form of the disease, dengue shock syndrome (DSS). The pathogenesis of DHF/DSS is not well understood, but epidemiological observations suggest that disease severity is associated with secondary infection with heterologous dengue serotypes. The objective of this research project is to study the role of CD4+ and CD8+ T lymphocytes in the human response to primary and sequential dengue infection, testing the overarching hypothesis that dengue virus (DV)-specific memory T cells may be preferentially activated by altered peptide ligands (APL) representing heterologous serotypes to produce proinflammatory cytokines or other soluble factors which may contribute to the immunopathogenesis of DHF/DSS. Our preliminary finding that memory CD8+ T cells from individuals with well defined dengue infections may be preferentially activated by APL representing previously encountered dengue virus to secrete enhanced levels of proinflammatory cytokines, coupled with altered cytolytic function, will be extended in a systematic analysis of cellular immunity in subjects with a known sequence of dengue virus infections. We will extend and confirm our findings that the polyclonal, heterogeneous DV-specific memory T cell population is capable of responding to a range of antigens, however at the clonal level the altered, skewed phenotype induced by stimulation with variant superagonist peptides, and the enhanced structural avidity for previously encountered antigens, may not necessarily be protective but may contribute to pathogenesis of dengue virus infection.

首席研究员/项目总监（姓、名、中）：Imrie, Allison 1 R21 AI074831-01A2 登革热在热带和亚热带地区流行，造成很高的发病率和死亡率。感染 4 种登革热病毒中的任何一种都可能无症状，也可能导致称为登革热的自限性发热性疾病。一小部分登革热病例进展为登革出血热 (DHF)，或该疾病最严重的形式——登革热休克综合征 (DSS)。 DHF/DSS 的发病机制尚不清楚，但流行病学观察表明疾病的严重程度与异源登革热血清型的继发感染有关。该研究项目的目的是研究 CD4+ 和 CD8+ T 淋巴细胞在人类对原发性和继发性登革热感染的反应中的作用，测试登革热病毒 (DV) 特异性记忆 T 细胞可能优先被改变的肽激活的总体假设配体（APL）代表异源血清型，产生促炎细胞因子或其他可溶性因子，可能有助于 DHF/DSS 的免疫发病机制。我们的初步发现是，来自明确登革热感染个体的记忆 CD8+ T 细胞可能会优先被代表先前遇到的登革热病毒的 APL 激活，以分泌增强水平的促炎细胞因子，同时改变细胞溶解功能，这一结果将得到扩展。对已知登革热病毒感染序列的受试者的细胞免疫进行系统分析。我们将扩展并证实我们的发现，即多克隆、异质 DV 特异性记忆 T 细胞群能够对一系列抗原做出反应，但在克隆水平上，由变体超激动剂肽刺激引起的改变、倾斜表型以及增强的对先前遇到的抗原的结构亲和力可能不一定具有保护性，但可能有助于登革热病毒感染的发病机制。