# The role of Interferon lambda signaling in flavivirus transmission and pathogenesis at the maternal-fetal interface

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $388,750

## Abstract

ABSTRACT
Antiviral immunity at the maternal-fetal interface involves a three-way interaction between the fetal-derived
placenta, the maternal decidua, and viral infection. This immunological balance promotes tolerance of the semi-
allogeneic fetus while protecting it from maternal pathogens. Zika virus (ZIKV), a mosquito-borne flavivirus, is
among the few microbes (termed TORCH pathogens) able to surmount the physical and immunological barrier
of the placenta to infect the developing fetus. However, the mechanisms by which ZIKV and other TORCH
pathogens overcome the protective antiviral response at the maternal-fetal interface are poorly understood.
Interferon lambda (IFN-λ) is a cytokine that contributes to antiviral immunity at anatomic barriers, including the
placenta. Studies with primary human placental trophoblasts, human placental explants, and mouse models of
congenital ZIKV infection have demonstrated a role for IFN-λ in antiviral immunity at the placental barrier.
However, we have found that IFN-λ also can induce fetal and placental pathology during congenital ZIKV
infection, an effect that results from IFN-λ signaling in maternal tissues. Furthermore, we found that
contemporary Asian-lineage ZIKV strains differ in their ability to induce IFN-λ-dependent pathology. This property
corresponds to enhanced sensitivity to IFN-γ in non-pregnant mice, as well as to the severity of disease observed
in non-human primate models of congenital ZIKV infection. We hypothesize that ZIKV strain-specific IFN-λ
responses regulate both protective antiviral responses in the placenta and pathologic maternal immune
responses. The balance between the protective and pathologic effects of IFN-λ signaling is important for
controlling TORCH pathogens such as ZIKV and rubella virus, as well as for autoimmune conditions associated
with elevated IFN production and poor pregnancy outcomes. We will define the IFN-λ specific antiviral response
in mice, placental cell lines, and primary human trophoblasts. We will determine whether ZIKV is better able to
antagonize this response compared to other flaviviruses and whether TORCH pathogens, such as ZIKV and
RUBV, share an ability to antagonize IFN-λ-mediated immunity in the placenta. We will use a mouse model of
congenital ZIKV infection to characterize the pathologic immune response elicited by maternal IFN-λ signaling
and generate conditional knockout lines to define the cell types that mediate this response. We will use reverse
genetics approaches to define the viral determinants of pathogenesis, particularly a role for a balanced
polymorphism in domain III of the viral E protein.

## Key facts

- **NIH application ID:** 10312708
- **Project number:** 5R01AI139512-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Helen Lazear
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312708

## Citation

> US National Institutes of Health, RePORTER application 10312708, The role of Interferon lambda signaling in flavivirus transmission and pathogenesis at the maternal-fetal interface (5R01AI139512-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10312708. Licensed CC0.

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