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.

概括怀孕女性的寨卡病毒（ZIKV）感染导致后代和长期感染发展出生缺陷。使用我们开发的免疫功能的鼠标模型（发表在自然通讯），我们已经表明，非洲，美国或亚洲的宫内感染早期但不晚的ZIKV菌株，妊娠会引起斑点和胎儿的感染，胎盘后代的炎症，新生儿皮质稀疏和短期神经系统防御。最近，我们有证明ZIKV感染的大坝中占地IL-1β浓度升高，我们可以逆转 ZIKV相关的短期神经性后遗症在后代中通过阻止IL-1受体信号传导感染。我们假设宫内ZIKV感染后的斑点注射会导致围产期神经损伤，可以通过靶向MATER IL-1β信号来逆转。而大多数zikv 干预措施集中于抗病毒药和疫苗以限制围产期ZIKV感染，迄今为止没有研究认为孕产妇和斑点炎症的作用是介导的长期不良的机制 ZIKV感染后的围产期结局。具体目标1将评估介导升高IL-的机制 ZIKV感染后，在不同胎龄的plapeta中的1β信号传导，长期下游位置免疫病理学和位置IL-1β信号的影响，以及这些影响是否是性别具体的。特别是，AIM 1将确定局部炎症体激活，IL-1β释放或 IL-1受体的参与导致围产期不良结果。特定目标2将检查孕产妇在围产期脑损伤的发病机理中与胎儿IL-1β信号的重要性 ZIKV感染后。使用IL-1β信号传导不足和野生型小鼠菌株的胚胎转移，AIM 2 将评估母体起源的IL-1β活性对于性别特异性胎儿脑损伤至关重要。我们的小说使用我们开发的ZIKV模型的转化研究建议将对围产作用，因为它将更好地理解位置感染在怀孕期间由感染或其他炎症状态引起的胎儿先天性疾病的发病机理。

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.