IL-1β regulation of Zika-mediated adverse perinatal outcomes

摘要 孕期女性感染寨卡病毒可致子代先天性感染及长期感染 发育性出生缺陷。使用我们开发的具有免疫能力的小鼠模型(发表在 自然传播)，我们已经表明，无论是非洲人、美国人还是亚洲人，宫内感染 ZIKV毒株在怀孕早期但不是晚期会引起胎盘、胎儿、胎盘的感染 炎症，新生儿皮质变薄，以及后代的短期神经功能缺陷。最近，我们已经 证实在感染寨卡病毒的水坝中胎盘IL-1β浓度升高，我们可以逆转 ZIKV阻断IL-1受体信号转导对子代短期神经行为后遗症的影响 感染。我们假设宫内感染寨卡病毒后的胎盘炎会导致围产儿。 神经损伤，然后可以通过靶向母体IL-1β信号来逆转。而大多数ZIKV 干预措施集中在限制围产期寨卡病毒感染的抗病毒药物和疫苗上，到目前为止还没有研究 认为母体和胎盘炎症是调节长期不良反应的一种机制 寨卡病毒感染后的围产儿结局。特定目标1将评估调节IL-1升高的机制 1寨卡病毒感染后不同胎龄胎盘中的β信号，长期下游 胎盘免疫病理和胎盘IL-1β信号的影响，以及这些影响是否与性别有关 具体的。特别是，AIM 1将确定胎盘炎症小体激活、IL-1β释放或 IL-1受体的参与会导致不良的围产儿结局。《特定目标2》将考察 母体而非胎儿IL-1β信号在围产期脑损伤发病机制中的重要性 在感染寨卡病毒之后。利用IL-1β信号缺陷和野生型小鼠品系的胚胎移植，目标2 将评估母体来源的IL-1β活性是否对特定性别的胎儿脑损伤至关重要。我们的小说 利用我们开发的ZIKV模型的翻译研究提案将对以下方面产生重大影响 围产期医学，因为它将导致更好地理解胎盘炎症在 妊娠期间感染或其他炎症状态引起的胎儿先天性疾病的发病机制。

SUMMARY Zika virus (ZIKV) infection of pregnant females results in congenital infection of offspring and long-term developmental birth defects. Using an immunocompetent mouse model that we developed (published in Nature Communications), we have shown that intrauterine infection with either African, American, or Asian strains of ZIKV during early, but not late, pregnancy causes infection of the placenta and fetuses, placental inflammation, neonatal cortical thinning, and short-term neurologic deficits in offspring. More recently, we have demonstrated that placental IL-1β concentrations are elevated in ZIKV-infected dams, and we can reverse the ZIKV-associated short-term neurobehavioral sequelae in offspring by blocking IL-1 receptor signaling during the infection. We hypothesize that placental inflammation following intrauterine ZIKV infection causes perinatal neurological injury, which can then be reversed by targeting maternal IL-1β signaling. While most ZIKV interventions focus on antivirals and vaccines to limit perinatal ZIKV infection, to date no studies have considered the role of maternal and placental inflammation as a mechanism mediating long-term adverse perinatal outcomes following ZIKV infection. Specific Aim 1 will assess the mechanisms mediating elevated IL- 1β signaling in the placenta at different gestational ages following ZIKV infection, the long-term downstream effects of the placental immunopathology and placental IL-1β signaling, and whether these effects are sex- specific. In particular, Aim 1 will determine how placental inflammasome activation, IL-1β release, or engagement of the IL-1 receptor lead to adverse perinatal outcomes. Specific Aim 2 will examine the importance of maternal as opposed to fetal IL-1β signaling in the pathogenesis of perinatal brain injury following ZIKV infection. Using embryo transfer of IL-1β signaling deficient and wild type mouse strains, Aim 2 will assess whether IL-1β activity of maternal origin is critical for sex-specific fetal brain injury. Our novel translational research proposal, utilizing a ZIKV model that we developed, will have a significant impact on perinatal medicine as it will lead to a better understanding of the role of placental inflammation in the pathogenesis of fetal congenital diseases caused by infection or other inflammatory states during pregnancy.