Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal-fetal interface

  1. Liheng Yang
  2. Eleanor C Semmes
  3. Cristian Ovies
  4. Christina Megli
  5. Sallie Permar
  6. Jennifer B Gilner
  7. Carolyn B Coyne  Is a corresponding author
  1. Duke University, United States
  2. University of Pittsburgh, United States
  3. Cornell University, United States

Abstract

Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed matched trophoblast and decidua organoids from human placentas to define the relative contributions of these cells to antiviral defenses at the maternal-fetal interface. We demonstrate that trophoblast and decidua organoids basally secrete distinct immunomodulatory factors, including the constitutive release of the antiviral type III interferon IFN-λ2 from trophoblast organoids, and differentially respond to viral infections through the induction of organoid-specific factors. Lastly, we define the differential susceptibility and innate immune signaling of trophoblast and decidua organoids to human cytomegalovirus (HCMV) and develop a co-culture model of trophoblast and decidua organoids which showed that trophoblast-derived factors protect decidual cells from HCMV infection. Our findings establish matched trophoblast and decidua organoids as ex vivo models to study vertically transmitted infections and highlight differences in innate immune signaling by fetal-derived trophoblasts and the maternal decidua.

Data availability

Sequence data have been deposited into Sequence Read Archives SUB11885513.

The following previously published data sets were used

Article and author information

Author details

  1. Liheng Yang

    Department of Molecular Genetics and Microbiology,, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6842-086X
  2. Eleanor C Semmes

    Department of Molecular Genetics and Microbiology,, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cristian Ovies

    Department of Molecular Genetics and Microbiology,, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christina Megli

    Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sallie Permar

    Department of Pediatrics, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jennifer B Gilner

    Department of Obstetrics and Gynecology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Carolyn B Coyne

    Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    For correspondence
    carolyn.coyne@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1884-6309

Funding

National Institute of Allergy and Infectious Diseases (NIHAI145828)

  • Carolyn B Coyne

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jan E Carette, Stanford University School of Medicine, United States

Publication history

  1. Preprint posted: March 30, 2021 (view preprint)
  2. Received: April 27, 2022
  3. Accepted: August 16, 2022
  4. Accepted Manuscript published: August 17, 2022 (version 1)
  5. Version of Record published: September 13, 2022 (version 2)

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,166
    Page views
  • 528
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Liheng Yang
  2. Eleanor C Semmes
  3. Cristian Ovies
  4. Christina Megli
  5. Sallie Permar
  6. Jennifer B Gilner
  7. Carolyn B Coyne
(2022)
Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal-fetal interface
eLife 11:e79794.
https://doi.org/10.7554/eLife.79794

Further reading

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease
    Olaya Rendueles, Jorge AM Moura de Sousa, Eduardo PC Rocha
    Research Article

    Many bacterial genomes carry prophages whose induction can eliminate competitors. In response, bacteria may become resistant by modifying surface receptors, by lysogenization, or by other poorly known processes. All these mechanisms affect bacterial fitness and population dynamics. To understand the evolution of phage resistance, we co-cultivated a phage-sensitive strain (BJ1) and a poly-lysogenic Klebsiella pneumoniae strain (ST14) under different phage pressures. The population yield remained stable after 30 days. Surprisingly, the initially sensitive strain remained in all populations and its frequency was highest when phage pressure was strongest. Resistance to phages in these populations emerged initially through mutations preventing capsule biosynthesis. Protection through lysogeny was rarely observed because the lysogens have increased death rates due to prophage induction. Unexpectedly, the adaptation process changed at longer time scales the frequency of capsulated cells in BJ1 populations increased again, because the production of capsule was fine-tuned, reducing the ability of phage to absorb. Contrary to the lysogens, these capsulated resistant clones are pan-resistant to a large panel of phages. Intriguingly, some clones exhibited transient non-genetic resistance to phages, suggesting an important role of phenotypic resistance in coevolving populations. Our results show that interactions between lysogens and sensitive strains are shaped by antagonistic co-evolution between phages and bacteria. These processes may involve key physiological traits, such as the capsule, and depend on the time frame of the evolutionary process. At short time scales, simple and costly inactivating mutations are adaptive, but in the long-term, changes drawing more favorable trade-offs between resistance to phages and cell fitness become prevalent.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Taylor B Engdahl, Elad Binshtein ... James E Crowe Jr.
    Research Article

    Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While infections in humans are relatively rare, mortality rates range from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the human humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity to authentic hantaviruses. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.