Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.
National Large Animal Research Facility, Singapore 769199, Singapore.
Sci Transl Med. 2023 Oct 25;15(719):eadd2420. doi: 10.1126/scitranslmed.add2420.
Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential of DENV-specific antibodies to enhance ZIKV disease severity in mice, we questioned whether maternal DENV immunity could influence fetal outcomes in a nonhuman primate model of ZIKV vertical transmission. We found significantly increased severity of congenital Zika syndrome (CZS) in fetuses of DENV-immune cynomolgus macaques infected with ZIKV in early pregnancy compared with naïve controls, which occurred despite no effect on maternal ZIKV infection or antibody responses. Ultrasound measurements of head circumference and biparietal diameter measurements taken sequentially throughout pregnancy demonstrated CZS in fetuses of DENV-immune pregnant macaques. Furthermore, severe CZS enhanced by DENV immunity was typified by reduced cortical thickness and increased frequency of neuronal death, hemorrhaging, cellular infiltrations, calcifications, and lissencephaly in fetal brains. This study shows that maternal immunity to DENV can worsen ZIKV neurological outcomes in fetal primates, and it provides an animal model of vertical transmission closely approximating human developmental timelines that could be used to investigate severe ZIKV disease outcomes and interventions in fetuses.
寨卡病毒（ZIKV）是一种蚊媒黄病毒，可通过母婴垂直传播，从而导致胎儿先天缺陷，包括小头畸形。目前尚不完全清楚为什么有些胎儿在子宫内暴露于寨卡病毒后会出现严重并发症，而另一些则不会。鉴于寨卡病毒与密切相关的登革热（DENV）病毒具有抗原相似性，并且 DENV 特异性抗体可能会增强小鼠中寨卡病毒的疾病严重程度，我们质疑母体 DENV 免疫是否会影响寨卡病毒垂直传播的非人灵长类动物模型中的胎儿结局。我们发现，与天真对照相比，在妊娠早期感染寨卡病毒的 DENV 免疫恒河猴胎儿中，先天性寨卡综合征（CZS）的严重程度明显增加，尽管这对母体寨卡病毒感染或抗体反应没有影响。整个妊娠期间连续进行的头围和双顶骨直径超声测量表明，DENV 免疫的怀孕恒河猴胎儿存在 CZS。此外，DENV 免疫增强的严重 CZS 的特征是皮质厚度降低，胎儿大脑中的神经元死亡、出血、细胞浸润、钙化和无脑回的频率增加。这项研究表明，母体对 DENV 的免疫可以使胎儿灵长类动物的寨卡病毒神经结局恶化，并提供了一种与人类发育时间接近的垂直传播动物模型，可用于研究胎儿中严重寨卡病毒疾病的结局和干预措施。
