Flaviviruses - Yin Yang of Heterologous T Cell Immunity

黄病毒-异源T细胞免疫的阴阳

基本信息

批准号：
7701544
负责人：
Sharone Green
金额：
$ 43.09万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7701544
关键词：
Avidity Biological Assay CD8B1 gene Categories Cell Culture Techniques Cell Line Cell Separation Cellular Immunity Clinical Collaborations Data Dengue Hemorrhagic Fever Dengue Virus Disease Encephalitis Viruses Endothelial Cells Epitopes Family Flaviviridae Flavivirus Flavivirus Infections Flow Cytometry Generations Human Immune Immune response Immunity Immunization In Vitro Incidence Individual Infection Japanese Encephalitis Viruses Japanese encephalitis virus Maintenance Measures Memory Methods Modeling Outcome Pathogenesis Pathology Pattern Peptide/MHC Complex Peptides Primates Reagent Research Project Grants Role Sampling Serotyping Signal Transduction South America Specificity System T-Lymphocyte T-Lymphocyte Epitopes Transgenic Mice Vaccines Variant Viral Viral Load result Virus Virus Diseases West Nile virus Yellow Fever Yellow fever virus Yin-Yang assay development cross reactivity disease characteristic hemorrhagic fever virus immunopathology in vivo insight meter mouse model novel pathogen response secondary infection technology development

项目摘要

The family Flaviviridae includes hemorrhagic fever viruses (e.g. dengue viruses, yellow fever virus) and encephalitis viruses (e.g. West Nile virus, Japanese encephalitis viruses). The long-term objective of this project is to determine the effect of flavivirus-specific CD4+ and CD8+ T cell responses induced by primary flavivirus infection on the immune response to subsequent infection with related flaviviruses. In Specific Aim 1, we will characterize effector responses, TCR avidity and signaling to homologous and heterologous virus CD4+ and CD8+ T cell epitopes in primary flavivirus-immune individuals. In Specific Aim 2, we will generate primary flavivirus CD4+ and CD8+ T cell responses to variant epitopes from flavivirus-naTve individuals and in human HLA transgenic mice. We will characterize cross-reactivity as in Aim 1 and will compare our findings in vitro to those generated in vivo. In Specific Aim 3, we will determine the biologic relevance of our in vitro findings. We will define variant specific responses in humans with sequential flavivirus infections. Using human HLA transgenic mice, we will model primary and secondary responses using peptide immunization followed by subclinical West Nile virus infection. Lastly, in collaboration with Project 2, we will determine the effect of variant T cell stimulation of human T cells on primary human endothelial cells. These studies will help to elucidate mechanisms of cross-protection and may give insights into disease pathogenesis.

Flaviviridae家族包括出血热病毒（例如登革热病毒，黄热病病毒）和脑炎病毒（例如西尼罗河病毒，日本脑炎病毒）。这个长期目标项目是为了确定一级诱导的黄病毒特异性CD4+和CD8+ T细胞反应的影响黄病毒感染对随后感染相关黄病毒的免疫反应。在特定的目标1中，我们将表征效应子响应，TCR亲和力以及对同源和原发性黄素免疫个体中的异源病毒CD4+和CD8+ T细胞表位。在特定的目标2中，我们将生成主要的黄病毒CD4+和CD8+ T细胞对变体表位的反应来自Flavivirus-natve个体和人类HLA转基因小鼠。我们将表征交叉反应性在AIM 1中，将在体外将我们的发现与体内产生的发现进行比较。在特定目标3中，我们将确定体外发现的生物学相关性。我们将定义变体具有顺序黄病毒感染的人类的特定反应。使用人HLA转基因小鼠，我们将使用肽免疫进行模型初级和次要反应，然后是亚临床西尼罗河病毒感染。最后，与项目2合作，我们将确定变异T细胞刺激的影响原代人内皮细胞上的人类T细胞。这些研究将有助于阐明交叉保护的机制，并可能对疾病进行见解发病。