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IL-1B regulation of Zika-Mediated adverse perinatal outcomes

IL-1B 对寨卡介导的不良围产期结局的调节

基本信息

批准号：
10782381
负责人：
IRINA BURD
金额：
$ 32.05万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10782381
关键词：
IL 1B regulation Zika Mediated

项目摘要

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.

总结孕妇感染寨卡病毒（ZIKV）会导致后代先天性感染，发育性出生缺陷。使用我们开发的免疫活性小鼠模型（发表于自然通讯），我们已经表明，无论是非洲人，美洲人，还是亚洲人，在妊娠早期而非晚期，ZIKV株引起胎盘和胎儿感染，胎盘感染炎症、新生儿皮质变薄和后代短期神经功能缺损。最近，我们有研究表明，胎盘IL-1β浓度在ZIKV感染的母鼠中升高，我们可以逆转这种情况。 ZIKV相关的短期神经行为后遗症在后代中通过阻断IL-1受体信号传导，感染我们假设子宫内ZIKV感染后的胎盘炎症导致围产期神经损伤，然后可以通过靶向母体IL-1β信号转导来逆转。虽然大多数ZIKV 干预措施集中在抗病毒药物和疫苗，以限制围产期ZIKV感染，迄今为止，没有研究认为母体和胎盘炎症的作用是介导长期不良反应的机制， ZIKV感染后的围产期结局。特异性目的1将评估介导IL-2升高的机制。 ZIKV感染后不同胎龄胎盘中的1β信号传导，胎盘免疫病理学和胎盘IL-1β信号传导的影响，以及这些影响是否与性别有关。特定.特别是，Aim 1将确定胎盘炎性小体激活、IL-1β释放或 IL-1受体的参与导致不良的围产期结果。具体目标2将审查母体与胎儿IL-1β信号在围产期脑损伤发病机制中的重要性 ZIKV感染后。利用IL-1β信号转导缺陷小鼠和野生型小鼠的胚胎移植，将评估母体来源的IL-1β活性是否对性别特异性胎儿脑损伤至关重要。我们的新型利用我们开发的ZIKV模型的转化研究提案将对围产期医学，因为它将导致更好地了解胎盘炎症的作用，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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Influenza subtype-specific maternal antibodies protect offspring against infection but inhibit vaccine-induced immunity and protection in mice.

DOI：
10.1016/j.vaccine.2022.10.003
发表时间：
2022-11-08
期刊：
VACCINE
影响因子：
5.5
作者：
Creisher, Patrick S;Campbell, Ariana D;Perry, Jamie L;Roznik, Katerina;Burd, Irina;Klein, Sabra L
通讯作者：
Klein, Sabra L

Dose-dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy.