The first trimester human placenta responds to Zika virus infection inducing an interferon (IFN) and antiviral interferon stimulated gene (ISG) response
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Date
2025
Authors
Van Der Hoek, K.H.
Jankovic-Karasoulos, T.
McCullough, D.
Coldbeck-Shackley, R.C.
Eyre, N.S.
Roberts, C.T.
Beard, M.R.
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Virology Journal, 2025; 22(1):108-1-108-15
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Kylie H. Van der Hoek, Tanja Jankovic-Karasoulos, Dylan McCullough, Rosa C. Coldbeck-Shackley, Nicholas S. Eyre, Claire T. Roberts and Michael R. Beard
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Abstract
Background: Zika virus (ZIKV) is a positive-strand RNA virus of the Flaviviridae family. Maternal ZIKV infection during pregnancy can spread to the placenta and fetus causing severe neurological defects and infants born with microcephaly. Here, we investigated ZIKV infection and the cellular innate antiviral immune response in first trimester human placental explant cultures and isolated primary villus cytotrophoblasts (CTBs). Methods: Placentas were obtained with informed consent from women undergoing elective pregnancy termination and either cultured as placental explants or used to isolate primary CTBs. Explants and CTBs were both infected with ZIKV (PRVABC59), and samples evaluated for infection by qRT-PCR, viral plaque and ELISA assays, and immunohistochemical or immunocytochemical staining. Results: We demonstrate robust infection and production of ZIKV in placental explant and CTB cultures. Both displayed delayed upregulation of interferons (IFN), most notably IFNβ and IFNλ2/3, and a panel of interferon stimulated genes (ISG) (IFI6, IFIT1, IFIT2, IFITM1, ISG15, MX1, RSAD). Stimulation of explants and CTBs with the dsRNA mimic poly(I: C), caused immediate IFN and ISG upregulation, demonstrating the first trimester placenta is innate immune competent. This suggests that either ZIKV blocks the early innate response, or the placental response is inherently hindered. Conclusion: Together these data show that first trimester placenta is susceptible to ZIKV infection which induces a delayed type III IFN antiviral response. This delay likely creates an environment favourable to ZIKV replication and dissemination across the early gestation placenta to fetal tissue, causing pathologies associated with congenital ZIKV syndrome.
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Published online: 19 April 2025
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© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.