# Mechanisms of Endometrial Innate Immune Responses to Infection and Impact on Placental Interactions

> **NIH NIH R00** · YALE UNIVERSITY · 2024 · $105,729

## Abstract

PROJECT SUMMARY (of the Parent Award)
Spontaneous pregnancy loss is the most common early obstetric complication, affecting 1 in 4 women worldwide.
While ~50% of cases are due to fetal chromosomal abnormalities, the causes for the other ~50% remain unclear,
although there is increasing evidence that a dysfunctional maternal endometrium may play a role. Bacterial and
viral infections have been associated with ~15% of early pregnancy losses, as well as later gestational
complications such as preterm birth and preeclampsia. However, how the maternal endometrium intrinsically
responds to infection remains unclear, highlighting a major gap in knowledge. Endometrial stromal cells (EnSCs)
are the major cellular component of the endometrium and they undergo a specialized differentiation process,
termed decidualization, monthly in anticipation of pregnancy. If pregnancy ensues, EnSCs play key roles in
regulating blastocyst implantation and placental trophoblast invasion at the maternal-fetal interface. Thus,
appropriate EnSC function is crucial to the establishment of a healthy pregnancy. EnSCs are likely to affect
trophoblast function through a combination of soluble factor secretion and production of extracellular vesicles
(EVs) which mediate intercellular communication through their protein, nucleic acid, and lipid cargos. This
research proposes to take a focused mechanistic approach to investigate how a viral infection affects EnSC
decidualization, EV production and interactions with trophoblasts using viral dsRNA [Poly(I:C)] as a model. In
preliminary studies, we found that Poly(I:C) reduced EnSC decidualization whilst increasing senescence and EV
production. Poly(I:C)-exposed EnSCs also had reduced capacity to chemoattract trophoblasts. Based on this,
our central hypothesis is that viral infection prevents adequate EnSC decidualization and accelerate senescence,
leading to increased EV production by EnSCs. Together, this results in altered EnSC interactions with
trophoblasts, impairing implantation and placentation. Our specific aims are to: examine the mechanisms by
which Poly(I:C) affects EnSC decidualization and senescence (Aim 1); determine the effects of early Poly(I:C)
exposure on pregnancy progression and outcome in vivo (Aim 2); and determine how Poly(I:C) affect EnSC EV
production and subsequent effects on trophoblasts (Aim 3). This project enables the candidate to combine her
backgrounds in reproductive immunology, early placental development and endometrial biology with her
interests in EVs as a novel mode of intercellular communication at the maternal-fetal interface. These studies
are significant because they will provide novel mechanistic insights into how infection impacts EnSC
decidualization and their subsequent interactions with placental trophoblasts, establishing a strong link between
infection, endometrial dysfunction, implantation failure and the myriad of obstetric complications associated with
impaired placentation. Thus, suc...

## Key facts

- **NIH application ID:** 11089993
- **Project number:** 3R00HD101653-05S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mancy Tong
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $105,729
- **Award type:** 3
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11089993

## Citation

> US National Institutes of Health, RePORTER application 11089993, Mechanisms of Endometrial Innate Immune Responses to Infection and Impact on Placental Interactions (3R00HD101653-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11089993. Licensed CC0.

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