T cell response to Dengue virus serotype 3 in mice and humans

小鼠和人类中 T 细胞对登革热病毒血清型 3 的反应

基本信息

批准号：
8375880
负责人：
Sujan Shresta
金额：
$ 40.69万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8375880
关键词：
Animal Model Antibodies Antibody Formation Antiviral Agents Asia Biological Assay CD8B1 gene Cell Line Cells Collaborations Consensus Sequence Country Culicidae Cytokine Activation Data Dengue Dengue Hemorrhagic Fever Dengue Shock Syndrome Dengue Virus Disease Epidemic Epidemiologic Studies Epitopes Equilibrium Genotype Human Human Volunteers Immune response Immunity Immunization Individual Infection Interferons Latin America Mediating Modeling Mus Nature Pathogenesis Pathology Peptides Peripheral Blood Mononuclear Cell Production Research Role Sampling Serotyping Specificity Splenocyte T cell response T memory cell T-Lymphocyte Testing Transgenic Mice Vaccines Variant Viral Viral Proteins Virus Virus Diseases base biodefense cytotoxic enzyme linked immunospot assay gain of function immunopathology in vivo loss of function mouse model receptor response therapy development vaccine candidate

项目摘要

The four serotypes of Dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in humans. Studies suggest that DHF/DSS is an immunopathogenic disease in which T cell responses may be dysregulated. Understanding the mechanisms that regulate the balance between T cell mediated pathology versus protection is crucial for developing therapies and, importantly, a safe dengue vaccine. By alternately passaging a DENV between mice and mosquito cells, we have naturally selected for strains that induce robust T cell responses in mice, and we have demonstrated a critical role for CD8+ T cells in limiting DENV infection in mice. Due to the broad specificity and antiviral role of the CD8+ T cell response to DENV2 in mice, we hypothesize that the murine and human CD8+ T cell response to DENV3 is broad, targeting most viral proteins, and these CD8+ T cells protect against DENV3 infection in the host. Specifically, we will examine the contribution of CD8+ T cells to protection versus pathogenesis using a mouse model of DENV3 infection (Aims 1 and 2), and we will define the specificity and role of human CD8+ T cell response in the host response to DENV3 infection using HLA transgenic mice and samples derived from people who have recovered from primary DENV3 infection (Aims 3 and 4). This project focuses on DENV3 because epidemiologic studies suggest that certain DENV serotypes, genotypes, and the sequence of DENV infections may be associated with DHF/DSS, and little is known about DENV3 infection as compared with DENV2, although DENV3 co-circulates with DENV2 in endemic countries, and DENV3 has been responsible for recent epidemics in South Asia and Latin America.

登革热病毒（DENV）的四种血清型引起登革热（DF）和登革热出血人类的发烧/登革热综合症（DHF/DSS）。研究表明DHF/DSS是 T细胞反应可能失调的免疫致病性疾病。了解调节T细胞介导的病理与保护之间平衡的机制对于开发疗法，重要的是一种安全的登革热疫苗。通过交替散发DENV 在小鼠和蚊子细胞之间，我们自然选择了诱导强大T细胞的菌株小鼠的反应，我们在限制DENV感染中证明了CD8+ T细胞的关键作用在老鼠中。由于CD8+ T细胞对DENV2在小鼠中的特异性和抗病毒作用的广泛特异性和抗病毒作用，我们假设鼠和人类CD8+ T细胞对DENV3的反应很广，针对大多数病毒蛋白质，这些CD8+ T细胞可以防止宿主中的DENV3感染。具体来说，我们会的使用小鼠模型检查CD8+ T细胞对保护与发病机理的贡献 DENV3感染（目标1和2），我们将定义人CD8+ T细胞的特异性和作用使用HLA转基因小鼠对宿主对DENV3感染的反应和源自从原发性DENV3感染中恢复的人（目标3和4）。这个项目重点 DENV3由于流行病学研究表明某些DENV血清型，基因型和 DENV感染的序列可能与DHF/DSS有关，对DENV3知之甚少与DENV2相比，感染，尽管DENV3在地方性国家与DENV2共同循环，但 DENV3负责南亚和拉丁美洲最近的流行病。