Flaviviruses: Yin-yang of Heterologous Immunity

黄病毒：异源免疫的阴阳

基本信息

批准号：
7698549
负责人：
Sharone Green
金额：
$ 43.04万
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：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7698549
关键词：
Address Adult Antibodies Antibody Formation Antigens Attenuated Biological Biological Markers CD8-Positive T-Lymphocytes CD8B1 gene Categories Cell division Cell physiology Clinical Dengue Dengue Virus Detection Development Disease Encephalitis Viruses Epitopes Facility Construction Funding Category Family Flaviviridae Flavivirus Flavivirus Infections Gene Proteins Genes Human Immune Immune response Immunity Immunization Immunological Models Immunologics Individual Infection Japanese Encephalitis Viruses Japanese encephalitis virus Kinetics Life Memory Methodology Methods Modeling National Institute of Allergy and Infectious Disease Nature Nonstructural Protein Peripheral Blood Mononuclear Cell Production Proteomics Sampling Secondary Immunization Secondary to Severity of illness Structural Protein T memory cell T-Lymphocyte T-Lymphocyte Epitopes Transgenic Mice Vaccination Vaccines Vertebral column Viral Viremia Virus West Nile virus Yellow Fever Yin-Yang assay development chimeric antibody cross reactivity cytokine hemorrhagic fever virus high throughput screening memory recall neutralizing antibody new technology novel novel strategies novel vaccines pathogen recombinant virus vaccine response secondary infection technology development vaccine development vector

项目摘要

The family Flaviviridae includes over 60 human pathogens, including hemorrhagic fever viruses [e.g. dengue, yellow fever (YF)] and encephalitis viruses [e.g. West Nile virus, Japanese encephalitis virus (JE)]. These viruses have a high degree of homology and immunologic crossreactivity. 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 other flaviviruses. Sequential flavivirus infections occur in nature and there are examples of cross-protection as well as enhanced disease in secondary flavivirus infections. In Aim 1, we plan to identify novel flavivirus-specific CD4+ and CD8+ T cell epitopes. We will then characterize effector responses (cytokine production, proliferation) to homologous and heterologous viruses. In Aim 2, we will use two closely related viruses to model the immunologic effects of sequential flavivirus infection" yellow fever (YF)17D and a candidate Japanese encephalitis virus (JE) vaccine comprised of a live attenuated chimeric YF that contains the premembrane (prM) and envelope (E) regions of a heterologous flavivirus, JE. We will quantitate the epitope-specific T cell responses in primary and secondary flavivirus infection, and determine whether secondary infections alter the T cell epitope hierarchy to memory/recall (nonstructural) or novel/na'fve (structural) antigens. In Aim 3, we will examine associations during primary and secondary immunization with YF17D and chimeric YF/JE between flavivirus-specific T cell responses and viremia and antibody responses. These studies will help to elucidate beneficial and detrimental aspects of heterologous viral immunity and will help in the development of novel vaccines against these biological threats.

Flaviviridae家族包括60多个人类病原体，包括出血热病毒[例如登革热，黄热病（YF）]和脑炎病毒[例如西尼罗河病毒，日语脑炎病毒（JE）]。这些病毒具有高度的同源性和免疫学交叉反应性。该项目的长期目标是确定黄病毒特异性的影响原发性黄素感染引起的CD4+和CD8+ T细胞反应对免疫反应随后感染其他黄素病毒。顺序的黄病毒感染发生在自然界中，有跨保护和疾病增强的例子感染。在AIM 1中，我们计划确定新型的黄病毒特异性CD4+和CD8+ T细胞表位。我们然后将表征效应子反应（细胞因子产生，增殖）对同源和异源病毒。在AIM 2中，我们将使用两种密切相关的病毒对免疫学建模顺序黄病毒感染的影响“黄热病（YF）17d和候选人日语脑炎病毒（JE）疫苗，该疫苗由含有前膜的活嵌合体YF组成（PRM）和信封（e）异源黄病毒的区域，JE。我们将量化原发性和继发黄病毒感染中的表位特异性T细胞反应，并确定继发感染是将T细胞表位层次结构改变为记忆/回忆（非结构性）还是新颖/na'fve（结构）抗原。在AIM 3中，我们将研究初级和在黄病毒特异性T细胞之间使用YF17D和嵌合YF/JE进行二次免疫反应，病毒血症和抗体反应。这些研究将有助于阐明有益和异源病毒免疫的有害方面，将有助于发展新颖针对这些生物威胁的疫苗。