SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas

Ishani Wickramage; Jeffrey VanWye; Klaas Max; John H Lockhart; Ismet Hortu; Ezinne F Mong; John Canfield; Hiran M Lamabadu Warnakulasuriya Patabendige; Ozlem Guzeloglu-Kayisli; Kimiko Inoue; Atsuo Ogura; Charles J Lockwood; Kemal M Akat; Thomas Tuschl; Umit A Kayisli; Hana Totary-Jain

doi:10.1016/j.chom.2023.05.018

SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas

Cell Host Microbe. 2023 Jul 12;31(7):1185-1199.e10. doi: 10.1016/j.chom.2023.05.018. Epub 2023 Jun 13.

Authors

Ishani Wickramage¹, Jeffrey VanWye¹, Klaas Max², John H Lockhart¹, Ismet Hortu¹, Ezinne F Mong¹, John Canfield¹, Hiran M Lamabadu Warnakulasuriya Patabendige³, Ozlem Guzeloglu-Kayisli⁴, Kimiko Inoue⁵, Atsuo Ogura⁵, Charles J Lockwood⁴, Kemal M Akat⁶, Thomas Tuschl², Umit A Kayisli⁴, Hana Totary-Jain⁷

Affiliations

¹ Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
² Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
³ Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
⁴ Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33602, USA.
⁵ Bioresource Engineering Division, BioResource Research Center, RIKEN, Tsukuba 305-0074, Ibaraki, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Ibaraki, Japan.
⁶ Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY 10065, USA; Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; USF Heart Institute, University of South Florida, Tampa, FL 33602, USA. Electronic address: totaryjainh@usf.edu.

PMID: 37315561
PMCID: PMC10524649 (available on 2024-07-12)
DOI: 10.1016/j.chom.2023.05.018

Abstract

Hemochorial placentas have evolved defense mechanisms to prevent the vertical transmission of viruses to the immunologically underdeveloped fetus. Unlike somatic cells that require pathogen-associated molecular patterns to stimulate interferon production, placental trophoblasts constitutively produce type III interferons (IFNL) through an unknown mechanism. We demonstrate that transcripts of short interspersed nuclear elements (SINEs) embedded in miRNA clusters within the placenta trigger a viral mimicry response that induces IFNL and confers antiviral protection. Alu SINEs within primate-specific chromosome 19 (C19MC) and B1 SINEs within rodent-specific microRNA cluster on chromosome 2 (C2MC) produce dsRNAs that activate RIG-I-like receptors (RLRs) and downstream IFNL production. Homozygous C2MC knockout mouse trophoblast stem (mTS) cells and placentas lose intrinsic IFN expression and antiviral protection, whereas B1 RNA overexpression restores C2MCΔ/Δ mTS cell viral resistance. Our results uncover a convergently evolved mechanism whereby SINE RNAs drive antiviral resistance in hemochorial placentas, placing SINEs as integral players in innate immunity.

Keywords: C19MC; C2MC; antiviral immunity; convergent evolution; placenta; retrotransposons; vertical transmission.

MeSH terms

Animals
Antiviral Agents
Female
Interferon Lambda
Mice
MicroRNAs* / genetics
Placenta
Pregnancy
Short Interspersed Nucleotide Elements

Substances

MicroRNAs
Interferon Lambda
Antiviral Agents

Grants and funding

R01 HL128411/HL/NHLBI NIH HHS/United States