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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：
7671900
负责人：
Sujan Shresta
金额：
$ 18.58万
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：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7671900
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 Latin America Mediating Modeling Mus Nature Pathogenesis Pathology Peptides Peripheral Blood Mononuclear Cell Production Research Role Sampling Serotyping Specificity Splenocyte 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）的四种血清型可引起登革热（DF）和登革出血热