# Mechanisms of trophoblast-induced immune modulation

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $385,000

## Abstract

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...

## Key facts

- **NIH application ID:** 9999396
- **Project number:** 5R01AI145829-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** GIL G MOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2019-08-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999396

## Citation

> US National Institutes of Health, RePORTER application 9999396, Mechanisms of trophoblast-induced immune modulation (5R01AI145829-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999396. Licensed CC0.

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