Seroepidemiologic risk for congenital Zika syndrome and adaptive immunity of fetal infection

摘要 感染孕妇后，寨卡病毒（ZIKV）可能会穿过胎盘，感染胎儿并导致国外 一系列出生缺陷，包括小头畸形、生长受限、胎儿死亡、关节弯曲和视力， 听力（先天性寨卡综合征（CZS）），2015年有超过2500例病例。CZS的风险因素包括 在这场流行病之后的许多未知之中。假设和主要关注的是， 由先前登革热（DENV）感染引起的抗体（Ab）可与ZIKV交叉反应并使疾病恶化 表型类似于在严重的继发性DENV感染中观察到的Ab依赖性增强（ADE）。 确定DENV免疫力是否是CZS的风险因素是下一步的当务之急。具体目标1 该提案将确定DENV免疫状态是否是CZS的风险修饰因子。为了有效地产生 可靠的流行病学数据，将利用正在进行的队列研究进行病例对照研究， 尼加拉瓜和哥伦比亚。DENV免疫状态将通过我们提供的独特方法来表征 实验室允许检测类型特异性抗体，反映个人的黄病毒暴露史。作为 作为一个子目标，我们将验证脐带血作为一种方便的样本，用于进行血清学检测， 母亲的黄病毒抗体反应。由于对胎儿的免疫反应知之甚少， ZIKV，我们将在具体目标2中评估来自脐带血的胎儿T和B细胞的功能和表型。是 已知先天性巨细胞病毒感染中T细胞表型改变，我预测， 与未感染的婴儿相比，CZS婴儿的脐带血中存在效应和记忆T细胞。 对照在多克隆表达后，也可能观察到分泌效应细胞因子的更大能力。 刺激.抗原特异性T细胞应答将通过测量对ZIKV的细胞因子分泌来定量。 抗原特异性B细胞将通过改良的ELISPOT技术定量， 激活胎儿记忆B细胞。具体目标1承诺提供实用知识，以改善公众 用于监测ZIKV的健康和临床方法。它还提供了重要的信息，以维护安全， DENV和ZIKV疫苗的开发和实施。目的2可以识别免疫相关的 病理或感染，具有诊断或预后效用。基于免疫的干预措施的目标， ZIKV暴露的妊娠也可能被发现。

ABSTRACT Upon infecting a pregnant woman, Zika virus (ZIKV) may cross the placenta, infect the fetus and result in abroad array of birth defects including microcephaly, growth restriction, fetal demise, arthrogryposis, and vision and hearing (congenital Zika syndrome (CZS)) as seen with over 2500 cases 2015. The risk factors for CZS are among the many unknowns in the wake of this epidemic. The hypothesis and major concern is that maternal antibodies (Ab) elicited by prior dengue (DENV) infection may cross-react with ZIKV and exacerbate disease phenotypes similar to the Ab-dependent enhancement (ADE) observed in severe, secondary DENV infections. Determining whether DENV immunity is a risk factor for CZS is the imperative next step. Specific aim 1 of this proposal will determine whether DENV immune status is a risk modifier for CZS. In order to efficiently generate reliable epidemiologic data, a case-control study will be conducted by leveraging ongoing cohort studies in Nicaragua and Colombia. The DENV-immune status will be characterized by unique methods available in our lab permitting the detection of type-specific antibodies that reflect an individual’s flavivirus exposure history. As a sub-aim, we will validate cord blood as a convenient sample for performing serologic assays that reflect the mother’s flavivirus antibody responses. Because little is known about fetal the immune response to congenital ZIKV, we will assess the function and phenotype of fetal T and B cells from cord blood in Specific aim 2. It is known that T cell phenotype is altered in congenital cytomegalovirus infection, I predict that a greater frequency of effector and memory T cells will be present in cord blood from infants with CZS compared to uninfected controls. A greater capacity to secrete effector cytokines is also likely to be observed following polyclonal stimulation. Antigen-specific T cell responses will be quantitated by measuring cytokine secretion to ZIKV- derived peptides; antigen-specific B cells will be quantitated by modified ELISPOT techniques following activation of fetal memory B cells. Specific aim 1 promises to yield practical knowledge for improving public health and clinical approaches for monitoring ZIKV. It also provides crucial information to maintain safety in development and implementation of vaccines to DENV and ZIKV. Aim 2 may identify immune correlates of pathology or infection that hold diagnostic or prognostic utility. Targets for immune-based interventions to protect ZIKV-exposed pregnancies may also be discovered.