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

摘要 寨卡病毒(ZIKV)感染孕妇后，可能会穿过胎盘，感染胎儿，导致国外感染 一系列出生缺陷，包括小头畸形、生长受限、胎儿死亡、关节畸形和视力 听力(先天性寨卡病毒综合征(CZS))2015年超过2500例。CZS的风险因素有 在这场疫情之后的许多未知因素中。假设和主要关注的是母体 先前感染登革热(DENV)引起的抗体(Ab)可能与寨卡病毒发生交叉反应并加剧疾病 表型类似于在严重的继发性DENV感染中观察到的抗体依赖增强(ADE)。 确定DENV免疫是否是CZS的危险因素是下一步的当务之急。具体目标1 提案将确定DENV免疫状态是否为CZS的风险修饰物。为了高效地生成 根据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的 实验室允许检测特定类型的抗体，以反映个人的黄病毒暴露史。AS 作为一个子目标，我们将验证脐带血作为一种方便的样本进行血清学分析，以反映 母亲的黄病毒抗体反应。因为人们对胎儿先天性免疫反应知之甚少 ZIKV，我们将在特定的目标2中评估脐带血中胎儿T和B细胞的功能和表型。 已知在先天性巨细胞病毒感染中T细胞表型改变，我预测更多的频率 与未感染的婴儿相比，CZS婴儿脐带血中存在大量的效应和记忆T细胞 控制。多克隆后也可能观察到更大的分泌效应性细胞因子的能力。 刺激。抗原特异性T细胞反应将通过测量细胞因子分泌到ZIKV- 衍生的多肽；抗原特异性B细胞将用改良的ELISPOT技术进行定量 胎儿记忆B细胞的激活。具体目标1承诺为改善公众提供实用知识 监测寨卡病毒的健康和临床方法。它还提供了维护安全的关键信息 DENV和ZIKV疫苗的开发和实施。AIM 2可能会识别免疫相关因素 具有诊断或预后作用的病理学或感染。基于免疫的干预措施的保护目标 暴露于寨卡病毒的怀孕也可能被发现。

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.