Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes

The placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional a...

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Main Authors: Lauren J. Johnson, Siavash Azari, Amy Webb, Xiaoli Zhang, Mikhail A. Gavrilin, Joanna M. Marshall, Kara Rood, Stephanie Seveau
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-07-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2021.709466/full
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spelling doaj-ce8a120a36d64893bb2ec41b51d39eb62021-07-23T11:22:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.709466709466Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy OutcomesLauren J. Johnson0Lauren J. Johnson1Siavash Azari2Siavash Azari3Amy Webb4Xiaoli Zhang5Mikhail A. Gavrilin6Joanna M. Marshall7Kara Rood8Stephanie Seveau9Stephanie Seveau10Stephanie Seveau11Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Microbiology, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Microbiology, The Ohio State University, Columbus, OH, United StatesDepartment of Biomedical Informatics, The Ohio State University, Columbus, OH, United StatesDepartment of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, United StatesPulmonary, Critical Care and Sleep Medicine Division, Department of Internal Medicine, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Microbiology, The Ohio State University, Columbus, OH, United StatesInfectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesThe placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional and waste exchanges between the mother and fetus. The bacterial pathogen Listeria monocytogenes breaches the trophoblast barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. In this work, we analyzed the L. monocytogenes intracellular lifecycle in primary human trophoblasts. In accordance with previous studies, we found that the SYN is 20-fold more resistant to infection compared to mononuclear trophoblasts, forming a protective barrier to infection at the maternal interface. We show for the first time that this is due to a significant reduction in L. monocytogenes uptake by the SYN rather than inhibition of the bacterial intracellular division or motility. We here report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts (RNA sequencing). Pathway analysis showed that infection upregulated TLR2, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-κB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFα, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFα). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.https://www.frontiersin.org/articles/10.3389/fimmu.2021.709466/fulltrophoblastfusionplacentaListeria monocytogenesinfectioninflammation
collection DOAJ
language English
format Article
sources DOAJ
author Lauren J. Johnson
Lauren J. Johnson
Siavash Azari
Siavash Azari
Amy Webb
Xiaoli Zhang
Mikhail A. Gavrilin
Joanna M. Marshall
Kara Rood
Stephanie Seveau
Stephanie Seveau
Stephanie Seveau
spellingShingle Lauren J. Johnson
Lauren J. Johnson
Siavash Azari
Siavash Azari
Amy Webb
Xiaoli Zhang
Mikhail A. Gavrilin
Joanna M. Marshall
Kara Rood
Stephanie Seveau
Stephanie Seveau
Stephanie Seveau
Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
Frontiers in Immunology
trophoblast
fusion
placenta
Listeria monocytogenes
infection
inflammation
author_facet Lauren J. Johnson
Lauren J. Johnson
Siavash Azari
Siavash Azari
Amy Webb
Xiaoli Zhang
Mikhail A. Gavrilin
Joanna M. Marshall
Kara Rood
Stephanie Seveau
Stephanie Seveau
Stephanie Seveau
author_sort Lauren J. Johnson
title Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
title_short Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
title_full Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
title_fullStr Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
title_full_unstemmed Human Placental Trophoblasts Infected by Listeria monocytogenes Undergo a Pro-Inflammatory Switch Associated With Poor Pregnancy Outcomes
title_sort human placental trophoblasts infected by listeria monocytogenes undergo a pro-inflammatory switch associated with poor pregnancy outcomes
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2021-07-01
description The placenta controls the growth of the fetus and ensures its immune protection. Key to these functions, the syncytiotrophoblast (SYN) is a syncytium formed by fusion of underlying mononuclear trophoblasts. The SYN covers the placental surface and is bathed in maternal blood to mediate nutritional and waste exchanges between the mother and fetus. The bacterial pathogen Listeria monocytogenes breaches the trophoblast barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. In this work, we analyzed the L. monocytogenes intracellular lifecycle in primary human trophoblasts. In accordance with previous studies, we found that the SYN is 20-fold more resistant to infection compared to mononuclear trophoblasts, forming a protective barrier to infection at the maternal interface. We show for the first time that this is due to a significant reduction in L. monocytogenes uptake by the SYN rather than inhibition of the bacterial intracellular division or motility. We here report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts (RNA sequencing). Pathway analysis showed that infection upregulated TLR2, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-κB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFα, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFα). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.
topic trophoblast
fusion
placenta
Listeria monocytogenes
infection
inflammation
url https://www.frontiersin.org/articles/10.3389/fimmu.2021.709466/full
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