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：
8234188
负责人：
Sujan Shresta
金额：
$ 26.34万
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：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234188
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）和出血性登革热人类发烧/登革热休克综合症（DHF/DSS）。研究表明 DHF/DSS 是一种 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的平衡的机制对于开发治疗方法，最重要的是开发安全的登革热疫苗。通过交替传递 DENV 在小鼠和蚊子细胞之间，我们自然地选择了诱导强大 T 细胞的菌株小鼠反应，我们已经证明 CD8+ T 细胞在限制 DENV 感染中发挥着关键作用在小鼠中。由于小鼠体内 CD8+ T 细胞对 DENV2 反应的广泛特异性和抗病毒作用，我们假设小鼠和人类 CD8+ T 细胞对 DENV3 的反应广泛，针对大多数病毒这些 CD8+ T 细胞可以保护宿主免受 DENV3 感染。具体来说，我们将使用小鼠模型检查 CD8+ T 细胞对保护与发病机制的贡献 DENV3感染（目标1和2），我们将定义人类CD8+ T细胞的特异性和作用使用 HLA 转基因小鼠和来自以下来源的样品观察宿主对 DENV3 感染的反应从原发性 DENV3 感染中康复的人（目标 3 和 4）。该项目重点关注 DENV3，因为流行病学研究表明某些 DENV 血清型、基因型和 DENV 感染序列可能与 DHF/DSS 有关，但对 DENV3 知之甚少尽管 DENV3 与 DENV2 在流行国家共同传播，但与 DENV2 相比，感染率更高， DENV3 是最近南亚和拉丁美洲流行的罪魁祸首。