Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Hana Totary-Jain, Ph.D.

Committee Member

Burt Anderson, Ph.D.

Committee Member

Ozlem Guzeloglu-Kayisli, Ph.D.

Committee Member

Sami Noujaim, Ph.D.

Committee Member

Ying Yang, Ph.D.

Keywords

Short interspersed nuclear elements, placental antiviral immunity

Abstract

The evolution of hemochorial placentas in which the fetal trophoblast is bathed in maternal blood has vastly improved fetal development and survival in primates and rodents, due to the enhanced efficiency of nutrient, gas and waste exchange between the mother and the fetus. However, the extensive contact between the fetal tissues and maternal blood in these placentas also poses an increased risk of vertical transmission of pathogens such as viruses from the mother to the fetus. In response to this selection pressure, hemochorial placentas have evolved robust defense mechanisms to protect the immunologically naive fetus. Unlike somatic cells that require pathogen-associated molecular patterns to stimulate interferon (IFN) production, placental trophoblasts constitutively produce type III interferons (IFNL) through an unknown mechanism. Short interspersed nuclear elements (SINEs) are retrotransposons that constitute 13% of the human genome. Their functions are mostly unknown or considered deleterious. They were initially called “junk” DNA and their retrotransposition into genomic segments is known to cause deleterious consequences such as cancers. While they are now known to have some roles in gene regulation and evolution, the purpose of their evolutionary conservation while encompassing such a large percentage of the host genomes had remained a mystery. Primate-specific Alu SINEs and rodent-specific B1 SINEs are embedded in large miRNA clusters, the primate-specific chromosome 19 miRNA cluster (C19MC) and the rodent-specific chromosome 2 miRNA cluster (C2MC), respectively. In somatic tissues of primates, C19MC is epigenetically silenced by DNA methylation, while in rodent somatic tissues the C2MC is biallelically expressed. However, both C19MC and C2MC are exclusively expressed from the paternal allele, or are maternally-imprinted, in the primate and rodent placentas, respectively. Moreover, Alu SINEs and B1 SINEs, which are epigenetically silenced in somatic tissues and gain transcriptional activation only in response to stress conditions such as viral infections. Here we demonstrate that transcripts of these lineage-specific SINEs embedded in the maternally-imprinted miRNA clusters within the primate and rodent hemochorial placentas form dsRNA and trigger a viral mimicry response that induces IFNL and confers antiviral protection. We show that the C19MC Alu dsRNA activates RIG-I-like receptors (RLRs) and protein kinase R (PKR) and induces downstream IFNL production. Homozygous C2MC knockout mouse trophoblast stem (mTS) cells and placentas lose intrinsic IFN expression and antiviral protection, including viral vertical transmission in vivo, whereas B1 RNA overexpression restores C2MCΔ/Δ mTS cell viral resistance. Our results uncover a convergently evolved mechanism whereby SINE RNAs drive the type III IFN-mediated antiviral resistance in hemochorial placentas, placing SINEs as integral players in innate immunity.

Download

Share

COinS