Effect of polymicrobial infection on trophoblast-macrophage interactions

多种微生物感染对滋养层-巨噬细胞相互作用的影响

基本信息

批准号：
9120036
负责人：
GIL G MOR
金额：
$ 40.18万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120036
关键词：
Affect Bacteria Bacterial Infections Birth Cells Cessation of life Communication Complex Decidua Decision Making Environment Event Fetus General Population Guidelines Herpesviridae Human Immune Immunologics Immunosuppression Infection Inflammatory Response Interferon Type I Interferons Invaded Lead Maternal Mortality Microbe Modeling Molecular Mothers Mus NF-kappa B Natural Killer Cells Pathologic Pathway interactions Pattern recognition receptor Phenotype Placenta Placentation Population Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Premature Birth Prevention Production Receptor Activation Regulation Regulatory T-Lymphocyte Risk Role Signal Pathway Site Testing Tissues Viral Virus Virus Diseases Woman Work cell injury cytokine experience fetal immune function implantation macrophage microbial microorganism mortality mouse model pandemic disease pathogen prevent receptor receptor function response sensor success toll-like receptor 4 trophoblast

项目摘要

Pregnant women are more likely to experience severe complications, mortality and preterm birth, associated with viral infections compared with the general population. The presence of the placenta and the immunological adaptation of women to the fetus alter the immunologic response of the mother to microorganisms, although the reasons behind the increased susceptibility are poorly understood. The generalization of pregnancy as a condition of immune suppression is misleading and prevents the determination of adequate guidelines for treating pregnant women during pandemics. Therefore, it is important to better understand the unique immunologic conditions of pregnant women and how this population responds to viral and bacterial infections. The trophoblast, just like an innate immune cell, can recognize the presence of bacteria, viruses, and other microbes as well as dying cells and damaged tissue. Upon recognition, the trophoblast will often secrete a specific set of cytokines that in turn, will act upon the immune cells within the decidua (macrophages, Tregs, NK cells), "educating" them to work together in support of the growing fetus/placenta, or to defend against microbial invasion. Interestingly, trophoblast cells, as well as decidual macrophages display low sensitivity to bacterial products normally present, therefore preventing inflammatory response that could jeopardize the success of the pregnancy. Our central hypothesis is that viral infection of the placenta sensitizes the mother to bacterial products triggering an inflammatory response that induces pretenm birth and maternal mortality. The trophoblast, through the production of type I Interferons (IFN) is able to regulate maternal immune functions; to control a viral infection and prevent the transfer of virus to the fetus. However, following infection, the virus induces complex intracellular events that affect many components of host signaling pathways. Specifically we demonstrate that virus by inhibiting IFNBeta, is able to enhance Toll-like receptor 4 (TLR4) induced NF-kappaB activity, promoting an inflammatory response. We will elucidate: 1) the mechanism by which viral infection modulates the TLR4-NF-kappaB pathway in the trophoblast; 2) the effect of trophoblast viral infection on macrophage differentiation and function; and 3) the role of placenta-derived type I interferons on the maternal response to viral infection. Our specific aims are as follows: Aim 1. To determine the role of the type I interferon-TAM receptor pathway and Twist in the regulation of NF-kappaB in trophoblast cells. Aim 2. To Determine the mechanism by which virus changes trophoblast-macrophage crosstalk. Aim 3: Characterize the role of placental interferon in mortality and preterm birth using a murine model. Upon completion of these aims we will have a better understanding of how infection-associated preterm birth is the result of a polymicrobial infection and typically not due to infection by a single microorganism.

与普通人群相比，孕妇更有可能经历与病毒感染有关的严重并发症，死亡率和早产。胎盘的存在和妇女对胎儿的免疫适应改变了母亲对微生物的免疫学反应，尽管易感性提高背后的原因知之甚少。怀孕作为免疫抑制条件的概括是误导性的，并阻止了在大流行过程中对孕妇治疗的足够指南。因此，重要的是要更好地了解孕妇的独特免疫条件以及该人群如何应对病毒和细菌感染。像先天免疫细胞一样，滋养细胞可以识别细菌，病毒和其他微生物以及垂死的细胞和受损组织的存在。经过认识，滋养细胞通常会分泌一组特定的细胞因子，而这些细胞因子反过来又将作用于Decidua（巨噬细胞，Tregs，NK细胞）内的免疫细胞，“教育”它们共同支持胎儿/plocenta的增长或抗微生物的侵害。有趣的是，滋养细胞以及判决巨噬细胞对通常存在的细菌产物的敏感性低，因此可以防止炎症反应，从而危及怀孕的成功。我们的中心假设是，胎盘的病毒感染使母亲对细菌产物的敏感性触发炎症反应，从而诱导了人们的出生和孕产妇死亡。通过生产I型干扰素（IFN）能够调节母体免疫功能，滋养细胞。控制病毒感染并防止病毒转移到胎儿。但是，感染后，该病毒诱导了影响宿主信号途径许多组成部分的复杂细胞内事件。具体而言，我们通过抑制IFNBETA来证明病毒能够增强类似Toll样受体4（TLR4）诱导的NF-kappab活性，从而促进炎症反应。我们将阐明：1）病毒感染调节滋养细胞中TLR4-NF-kappab途径的机制； 2）滋养细胞病毒感染对巨噬细胞分化和功能的影响； 3）胎盘衍生的I型干扰素在母体对病毒感染的反应中的作用。我们的具体目的如下：目的1。确定I型干扰素TAM受体途径的作用和在滋养细胞中NF-kappab调节中的扭曲。目标2。确定病毒改变滋养细胞巨噬细胞串扰的机制。 AIM 3：使用鼠模型来表征胎盘干扰素在死亡率和早产中的作用。完成这些目标后，我们将更好地了解与感染相关的早产是多数菌感染的结果，通常不是由单一微生物感染。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High incidence of Zika virus infection detected in plasma and cervical cytology specimens from pregnant women in Guayaquil, Ecuador.

在厄瓜多尔瓜亚基尔孕妇的血浆和宫颈细胞学标本中检测到寨卡病毒感染率很高。

DOI：
10.1111/aji.12630
发表时间：
2017
期刊：
American journal of reproductive immunology (New York, N.Y. : 1989)
影响因子：
0
作者：
Zambrano,Hector;Waggoner,Jesse;León,Karina;Pinsky,Benjamin;Vera,Ketty;Schettino,Marissa;Rivera,Lisette;Landivar,José;Granda,María;Lee,Angela;Mor,Gil
通讯作者：
Mor,Gil

Cutting Edge: Fetal/Placental Type I IFN Can Affect Maternal Survival and Fetal Viral Load during Viral Infection.

最前沿：胎儿/胎盘 I 型干扰素可影响病毒感染期间母体存活率和胎儿病毒载量。

DOI：
10.4049/jimmunol.1601824
发表时间：
2017
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Racicot,Karen;Aldo,Paulomi;El-Guindy,Ayman;Kwon,Ja-Young;Romero,Roberto;Mor,Gil
通讯作者：
Mor,Gil

The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats.

PD-1/PD-L1 抑制通路在先兆子痫中发生改变并调节先兆子痫大鼠中的 T 细胞反应