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Mechanisms of trophoblast-induced immune modulation

滋养层诱导的免疫调节机制

基本信息

批准号：
10671640
负责人：
GIL G MOR
金额：
$ 38.5万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671640
关键词：
Animal Model Bacteria Cells Characteristics Cre lox recombination system Data Decidua Embryo Transfer Environment Feedback Fetus First Pregnancy Trimester Genes Genetic Transcription Guidelines Human Hypersensitivity IFNAR1 gene Immune Immune Evasion Immune response Immunologics In Vitro Infection Inflammation Inflammatory Inflammatory Response Interferons Invaded Knockout Mice Ligation Lipopolysaccharides Macrophage Maternal Mortality Maternal-Fetal Exchange Microbe Modeling Mothers Natural Killer Cells Nuclear Outcome Study Parasites Pathway interactions Pattern recognition receptor Placenta Pregnancy Pregnancy Complications Pregnant Women Production Receptor Activation Receptor Signaling Regulation Regulatory Pathway Regulatory T-Lymphocyte Risk Role Shapes Signal Transduction Site TLR2 gene TLR4 gene Testing Tissues Virus Virus Diseases Virus Replication blastocyst cytokine fetal immunoregulation implantation microbial novel novel therapeutic intervention pandemic disease pathogen predictive marker prevent receptor receptor function response sensor trophoblast type I interferon receptor

项目摘要

This application is in response to the RFA: AI-18-023 “Immune Mechanisms at the Maternal-Fetal Interface”. The trophoblast represents the first point of contact between the blastocyst and the maternal decidua and has an active role in shaping the immunological milieu at the implantation site. Trophoblast cells express pattern recognition receptors (PRR) that function as “sensors” of the surrounding environment. Through these receptors, the trophoblast can recognize bacteria, viruses, and other microbes as well as dying cells and damaged tissue. Type I IFN production is known to be a characteristic of the placenta in several species, including humans; and IFNβ is the predominant class, especially during the first trimester. In the context of pregnancy, we have shown that loss of IFNβ signaling in the placenta leads to: 1) uncontrolled viral replication and fetal viral infection, 2) maternal mortality and 3) hypersensitivity to bacterial products; suggesting a critical role of IFNβ signaling in the protection of pregnancy. Our central hypothesis is that placental IFNβ signaling is critical for the protection of the fetus and the mother during viral infections and because its ability to modulate TLRs’ responses can function as a major immune modulatory factor at the implantation site. The premise for this proposal is that in the trophoblast, there is an intrinsic cross talk between TLR2/4 and IFNβ pathway that provides protection against infection, but also prevents potential detrimental pro- inflammatory responses by inhibiting transcription of NF-κB regulated inflammatory cytokines. In addition, we have identified a novel mechanism of immune regulation in the trophoblast involving the TAM receptors, specifically the Axl receptor. The significance of these findings is in our premise that pathogens might hijack components of these pathways for purposes of microbial immune evasion. Pathogens such as viruses might inhibit IFNβ and enhance inflammation necessary for viral replication; or bacteria/parasites might promote IFNβ expression to inhibit NFκB-inflammation for cell infection. Our specific aims are: Aim 1. Determine how IFNβ interacts with Axl to regulate trophoblast inflammation. Aim 2. To characterize the mechanism by which IFNs and TAMs regulate transcription of NF-κB- dependent genes in the trophoblast. Aim 3. Define the impact of viral infections on the cross talk between Axl-IFNβ-TLR2/4 in animal models. Upon completion of these aims we will have a better understanding of the essential role for IFNβ and type I IFN receptor signaling in host responses to microbial infections during pregnancy. We will elucidate how IFNβ, and its regulatory pathways, such as TAM receptors, protect the fetus not only against viral infections but also prevents detrimental inflammatory responses. The outcome of these studies not only will enhance our understanding of the complexity of immune regulation at the maternal/fetal interface but also will provides novel opportunities for the identification of predictive markers and new therapeutic approaches by modulating IFNβ/TAM receptor signaling to protect pregnant women at risk to viral infections or during pandemics.

本申请是响应RFA: AI-18-023“母胎界面的免疫机制”。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peri-implantation cytokine profile differs between singleton and twin IVF pregnancies.

DOI：
10.1111/aji.13348
发表时间：
2021-03
期刊：
American journal of reproductive immunology (New York, N.Y. : 1989)
影响因子：
0
作者：
Simpson S;Kaislasuo J;Peng G;Aldo P;Paidas M;Guller S;Mor G;Pal L
通讯作者：
Pal L

Functional HLA-C expressing trophoblast spheroids as a model to study placental-maternal immune interactions during human implantation.

DOI：
10.1038/s41598-022-12870-6
发表时间：
2022-06-17
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

IL-10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses.

DOI：
10.1111/aji.13195
发表时间：
2020-01
期刊：
American journal of reproductive immunology (New York, N.Y. : 1989)
影响因子：
0
作者：
Kaislasuo J;Simpson S;Petersen JF;Peng G;Aldo P;Lokkegaard E;Paidas M;Pal L;Guller S;Mor G
通讯作者：
Mor G

Trophoblasts promote induction of a regulatory phenotype in B cells that can protect against detrimental T cell-mediated inflammation.