Bohm Ellie K, Castañeda David, Lu Qun, Cameron Michael D, Aliota Matthew T
Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, Minnesota, USA.
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida, USA.
J Virol. 2025 May 22:e0066625. doi: 10.1128/jvi.00666-25.
Congenital Zika syndrome (CZS), the set of fetal and neonatal complications associated with Zika virus (ZIKV) infection in pregnancy, was first noted during the outbreak in the Americas in 2015-2016. However, there was an unequal distribution of ZIKV cases and severe outcomes in all areas where ZIKV emerged in the Americas, demonstrating that the risk of CZS varied over space and time. Recently, we demonstrated that phenotypic heterogeneity existed between closely related ZIKV strains. All ZIKV strains tested infected the placenta but varied in their capacity to cause overt fetal harm. Here, we further characterized the relative contributions of virus genotype and infecting dose of two phenotypically distinct ZIKV strains across multiple timepoints in gestation in pregnant mice that lack type-I interferon receptor function (). To better understand the underlying causes of adverse fetal outcomes, we used RNA sequencing to compare ZIKV-infected and uninfected tissues. We found that ZIKV infection triggers retinoic acid-inducible gene I (RIG-I)-like receptor-mediated activation of the interferon response at the maternal-fetal interface. However, modest chemical inhibition of RIG-I activation in the decidua and placenta did not protect against fetal demise. Instead, the fetal interferon response was significantly associated with fetal demise. Together, these findings suggest that the response to ZIKV at the maternal-fetal interface can vary, depending on the infecting ZIKV genotype and dose, and that the fetal immune response is an important mediator of fetal harm.
Congenital Zika syndrome is a constellation of fetal abnormalities ranging from fetal demise and microcephaly to infants that are born apparently healthy only to develop neurocognitive impacts later. ZIKV is now endemic in many regions worldwide, but how ZIKV harms the developing fetus remains an outstanding question. Previously, we used a mouse model of ZIKV infection during pregnancy to assess the pathogenic potential to the fetus of a panel of five low-passage ZIKV strains representing the viral genetic diversity in the Americas. We found that phenotypic heterogeneity existed between these closely related ZIKV strains. Here, we show that this heterogeneity is driven by RIG-I-like receptor-mediated activation of the interferon response at the maternal-fetal interface. We used chemical inhibition of the RIG-I pathway and measured the transcriptional activity of interferon-stimulated genes in fetuses to demonstrate that the fetal immune response may contribute to fetal demise.
先天性寨卡综合征（CZS）是与孕期寨卡病毒（ZIKV）感染相关的一系列胎儿和新生儿并发症，于2015 - 2016年在美洲爆发期间首次被发现。然而，在美洲出现ZIKV的所有地区，ZIKV病例和严重后果的分布并不均匀，这表明CZS的风险随时间和空间而变化。最近，我们证明了密切相关的ZIKV毒株之间存在表型异质性。所有测试的ZIKV毒株都能感染胎盘，但导致明显胎儿损害的能力各不相同。在这里，我们进一步描述了两种表型不同的ZIKV毒株的病毒基因型和感染剂量在缺乏I型干扰素受体功能的怀孕小鼠孕期多个时间点的相对作用。为了更好地理解胎儿不良结局的潜在原因，我们使用RNA测序来比较ZIKV感染和未感染的组织。我们发现ZIKV感染在母胎界面触发了视黄酸诱导基因I（RIG-I）样受体介导的干扰素反应激活。然而，对蜕膜和胎盘RIG-I激活的适度化学抑制并不能预防胎儿死亡。相反，胎儿干扰素反应与胎儿死亡显著相关。总之，这些发现表明，母胎界面处对ZIKV的反应可能因感染的ZIKV基因型和剂量而异，并且胎儿免疫反应是胎儿损害的重要介导因素。
先天性寨卡综合征是一系列胎儿异常情况，从胎儿死亡、小头畸形到出生时看似健康但后来出现神经认知影响的婴儿。ZIKV现在在全球许多地区流行，但ZIKV如何损害发育中的胎儿仍然是一个突出问题。此前，我们使用孕期ZIKV感染的小鼠模型评估了代表美洲病毒基因多样性的一组五个低传代ZIKV毒株对胎儿的致病潜力。我们发现这些密切相关的ZIKV毒株之间存在表型异质性。在这里，我们表明这种异质性是由母胎界面处RIG-I样受体介导的干扰素反应激活驱动的。我们使用RIG-I途径的化学抑制并测量胎儿中干扰素刺激基因的转录活性，以证明胎儿免疫反应可能导致胎儿死亡。
