Dengue-Zika: Correlates of Cross-Protection in Non-Human Primates

登革热-寨卡：非人类灵长类动物交叉保护的相关性

基本信息

批准号：
10083183
负责人：
CARLOS A SARIOL
金额：
$ 69.54万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-09 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083183
关键词：
Adult Americas Animal Experiments Animal Model Animals Antibody-Dependent Enhancement Antigen-Antibody Complex Antiviral Agents Area B-Lymphocytes Behavior CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Caribbean region Cells Cellular Immunity Clinical Complement Data Dengue Dengue Infection Dengue Vaccine Dengue Virus Development Diagnosis Diagnostic Procedure Disease Outbreaks Epidemic Epidemiology Experimental Designs Exposure to Flavivirus Guillain Barré Syndrome Herd Immunity Human Immune Immune Sera Immune response Immune system Immunity Immunocompetent Immunodeficient Mouse Immunologics In Vitro Inbreeding Infection Inflammatory Link MS4A1 gene Macaca Macaca mulatta Mediating Modeling Newborn Infant Outcome Pathogenesis Play Population Pregnancy Primary Infection Primates Publications Research Role Series Serology System T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Vaccine Design Viremia Virus Virus Diseases Virus Replication Work ZIKA ZIKV disease ZIKV infection Zika Virus Zika virus vaccine cell type congenital zika syndrome cross reactivity cytokine design experimental group experimental study immunodeficient mouse model immunoregulation in vivo mosquito-borne nonhuman primate pathogen prevent protective effect response secondary infection secondary outcome severe dengue time interval tool viral transmission

项目摘要

Abstract Zika virus (ZIKV) is a re-emerging mosquito-borne Flavivirus that recently caused an outbreak in the Americas. The establishment of ZIKV transmission cycle in tropical/sub-tropical regions that are endemic to other close-related flaviviruses such as Dengue virus (DENV) has raised concerns, mainly by their cross-immunological interactions and the implications of this for development of severe clinical manifestations. Several groups have demonstrated that DENV-immune serum from humans can enhance ZIKV infection in vitro and in vivo in an immunodeficient mice model. This phenomenon known as Antibody Dependent-Enhancement (ADE) has been linked to severe dengue clinical manifestations. Little is known about the effect of a previous immunity to ZIKV on a subsequent DENV infection. It is highly necessary to characterize correlates of protection in the control of a heterologous secondary DENV or ZIKV infection in the presence of previous DENV or ZIKV immunity in an immunological competent animal model that resemble the human immune system like the Non- Human Primates. Our group have preliminary data showing a potential protective role of the cellular immune response in dengue- immune or ZIKV-immune subjects during a heterologous secondary infection with ZIKV or dengue. The overall hypothesis behind this work is that the cross-primed cellular immune response may be critical controlling the DENV and ZIKV infection and provides heterologous protection against each other. To test this hypothesis, we propose a series of straightforward experiments by depleting the CD4+ or CD8+ or CD20+ cells at different time points before a primary or a secondary infection with dengue or ZIKV. This type of experiment has not been performed before in NHP. For these experiments we will use rhesus macaques bred and housed at the Caribbean Primate Research Center that has proven to be the purer Indian-origin macaque population of all populations in the USA or imported animals, without having a significant level of inbreeding. For first time in any study in the flavivirus field, we will use a large data on the MHC typing of this population to characterize specific CD4 and/or CD8 T cells epitopes playing a role in the T cells immune response against dengue and ZIKV. Understanding correlates of protection between ZIKV and DENV is essential to anticipate the outcome of the secondary infection, the design of diagnostics methods and more relevant, to support the design of highly effective ZIKV and DENV vaccines in the scenario of previous DENV or ZIKV immunity, respectively. Undoubtedly, NHP provide us with a unique immunological tool very close to the human system to provide the answers to the questions we are outlying on this application.

抽象的寨卡病毒（ZIKV）是一种重新出现的蚊媒黄病毒，最近在美洲爆发了疫情。这在其他密切相关的黄病毒流行的热带/亚热带地区建立 ZIKV 传播周期诸如登革热病毒（DENV）等引起了人们的关注，主要是因为它们的跨免疫相互作用及其影响这可能会导致严重的临床表现。多个研究小组已证明 DENV 免疫血清来自人类的病毒可以在免疫缺陷小鼠模型中增强 ZIKV 的体外和体内感染。这种现象众所周知因为抗体依赖性增强（ADE）与严重的登革热临床表现有关。鲜为人知的是先前对 ZIKV 的免疫力对随后的 DENV 感染的影响。刻画相关性是非常有必要的在先前存在 DENV 或 ZIKV 的情况下控制异源继发性 DENV 或 ZIKV 感染的保护作用具有免疫能力的动物模型中的 ZIKV 免疫力类似于人类免疫系统，例如非人类灵长类动物。我们的小组有初步数据显示细胞免疫反应的潜在保护作用登革热免疫或 ZIKV 免疫受试者在 ZIKV 或登革热异源继发感染期间。整体这项工作背后的假设是，交叉引发的细胞免疫反应可能对于控制 DENV 和 ZIKV 感染并提供针对彼此的异源保护。为了检验这个假设，我们提出了一系列通过在初级或初级之前的不同时间点耗尽 CD4+ 或 CD8+ 或 CD20+ 细胞来进行简单的实验继发感染登革热或寨卡病毒。 NHP 此前从未进行过此类实验。对于这些我们将使用在加勒比灵长类动物研究中心饲养和饲养的恒河猴进行实验，该中心已被证明美国所有种群或进口动物中较纯正的印度原产猕猴种群，没有明显的近亲繁殖的程度。在黄病毒领域的所有研究中，我们将首次使用有关该病毒 MHC 分型的大量数据。群体来表征特定的 CD4 和/或 CD8 T 细胞表位，这些表位在 T 细胞免疫反应中发挥作用登革热和寨卡病毒。了解 ZIKV 和 DENV 之间保护的相关性对于预测结果至关重要继发感染的发生，诊断方法的设计更加相关，以支持高效的设计 ZIKV 和 DENV 疫苗分别是在以前的 DENV 或 ZIKV 免疫场景中。毫无疑问，NHP 提供我们拥有非常接近人类系统的独特免疫学工具，可以为我们所关心的问题提供答案在此应用程序上。