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

• 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
• 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

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子传播的黄病毒，最近在美洲爆发了爆发。这 在热带/亚热带地区建立ZIKV传输周期，这些周期是其他密切相关的黄病毒特有的 例如登革热病毒（DENV）引起了人们的关注，主要是由于它们的跨免疫相互作用及其含义 这是为了发展严重的临床表现。几个小组已经证明DENV-rimmune血清 从人类中可以在免疫缺陷的小鼠模型中增强体外和体内的ZIKV感染。这种现象已知 由于抗体依赖性增强（ADE）与严重的登革热临床表现有关。对 先前对ZIKV免疫对随后的DENV感染的影响。非常必要表征相关性 在存在先前的DENV或 ZIKV免疫中的免疫学胜任动物模型，类似于人类免疫系统，例如非 - 人类灵长类动物。我们的小组的初步数据显示了细胞免疫反应的潜在保护作用 ZIKV或登革热的异源继发感染期间，登革热或ZIKV-免疫受试者。总体 这项工作背后的假设是，跨染色的细胞免疫反应可能是控制DENV的关键，并且 ZIKV感染并提供异源保护。为了检验这一假设，我们提出了一系列 直接实验通过在主或A前面的不同时间点耗尽CD4+或CD8+或CD20+细胞 登革热或ZIKV的继发感染。在NHP之前，此类实验尚未进行。为此 实验我们将在加勒比灵长类动物研究中心使用Rhesus Macaques繁殖和安装 美国或进口动物的纯印度 - 印度猕猴种群，没有大量 近亲水平。在Flavivirus领域的任何研究中，我们将使用有关此MHC键入的大数据 人群表征特定的CD4和/或CD8 T细胞表现在T细胞免疫反应中起作用 登革热和Zikv。了解Zikv和DENV之间的保护相关性对于预期结果至关重要 二次感染，诊断方法的设计和更相关的，以支持高效的设计 在先前的DENV或ZIKV免疫的情况下，ZIKV和DENV疫苗。毫无疑问，NHP提供 我们的独特免疫工具非常接近人类系统 在此应用程序上。