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

Hemochorial placentas have evolved defense mechanisms to prevent 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 ty...

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Veröffentlicht in:Cell host & microbe 2023-06, Vol.31 (7), p.1185-1199.e10
Hauptverfasser: Wickramage, Ishani, VanWye, Jeffrey, Max, Klaas, Lockhart, John H., Hortu, Ismet, Mong, Ezinne F., Canfield, John, Lamabadu Warnakulasuriya Patabendige, Hiran M., Guzeloglu-Kayisli, Ozlem, Inoue, Kimiko, Ogura, Atsuo, Lockwood, Charles J., Akat, Kemal M., Tuschl, Thomas, Kayisli, Umit A., Totary-Jain, Hana
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Sprache:eng
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Zusammenfassung:Hemochorial placentas have evolved defense mechanisms to prevent 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 SINE within primate-specific chromosome 19 (C19MC) and B1 SINE within rodent-specific microRNA cluster on chromosome 2 (C2MC) produce dsRNA 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 C2MC Δ/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. Primates and rodents have hemochorial placentas with heightened risk of viral vertical transmission. Wickramage et al. uncovered a convergently evolved mechanism by which primate-specific Alu and rodent-specific B1 SINE RNA of the C19MC and the C2MC miRNA clusters, respectively, drive their placental constitutive type III interferon expression and antiviral protection.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2023.05.018