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IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection
Jun Lei, … , Sabra L. Klein, Irina Burd
Jun Lei, … , Sabra L. Klein, Irina Burd
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e122678. https://doi.org/10.1172/jci.insight.122678.
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Research Article Reproductive biology

IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

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Abstract

Zika virus (ZIKV) infection during pregnancy causes significant adverse sequelae in the developing fetus, and results in long-term structural and neurologic defects. Most preventive and therapeutic efforts have focused on the development of vaccines, antivirals, and antibodies. The placental immunologic response to ZIKV, however, has been largely overlooked as a target for therapeutic intervention. The placental inflammatory response, specifically IL-1β secretion and signaling, is induced by ZIKV infection and represents an environmental factor that is known to increase the risk of perinatal developmental abnormalities. We show in a mouse model that maternally administrated IL-1 receptor antagonist (IRA; Kineret, or anakinra), following ZIKV exposure, can preserve placental function (by improving trophoblast invasion and placental vasculature), increase fetal viability, and reduce neurobehavioral deficits in the offspring. We further demonstrate that while ZIKV RNA is highly detectable in placentas, it is not correlated with fetal viability. Beyond its effects in the placenta, we show that IL-1 blockade may also directly decrease fetal neuroinflammation by mitigating fetal microglial activation in a dose-dependent manner. Our studies distinguish the role of placental inflammation during ZIKV-infected pregnancies, and demonstrate that maternal IRA may attenuate fetal neuroinflammation and improve perinatal outcomes.

Authors

Jun Lei, Meghan S. Vermillion, Bei Jia, Han Xie, Li Xie, Michael W. McLane, Jeanne S. Sheffield, Andrew Pekosz, Amanda Brown, Sabra L. Klein, Irina Burd

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Figure 1

Historic and contemporary strains of ZIKV infect the placenta and cause placental dysfunction and developmental abnormalities in offspring.

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Historic and contemporary strains of ZIKV infect the placenta and cause ...
At E10, pregnant CD-1 mice received an intrauterine injection of 106 TCID50 units of the 2015 Brazil, 2015 Puerto Rico (PR), or 1968 Nigeria ZIKV, or vehicle (mock). (A) ZIKV RNA was isolated and quantified by qRT-PCR from placentas collected 48 hours after inoculation (48 hpi). (B) Representative fluorescence immunostaining for cytokeratin (black puncta, arrows) to label trophoblast cells in mock- or ZIKV-infected (Brazil strain) placentas. Right: High magnifications of black boxes (located in the mesometrial triangle) in the left panels. Scale bars: 1000 μm (left), 100 μm (right). (C) Quantitative analysis of trophoblast density (as a measure of trophoblast invasion) in the mesometrial triangle. (D) Representative fluorescence immunostaining for vimentin (red) to label endothelial cells in mock- or ZIKV-infected (Brazil strain) placentas. The right panels are high magnifications of the white boxes (located in the villi) in the left panels. Scale bars: 1000 μm (left), 100 μm (right). (E) Quantitative analysis of endothelial cell density in the placental villi. (F) Fetal viability quantified as the percentage of viable fetuses within the inoculated uterine horn (n = total number of fetuses from 4 to 5 dams per group). (G) Correlation between ZIKV RNA in placentas and fetal viability. (H–J) Representative images of limb contracture (arthrogryposis) (H), fused digits (syndactyly) (I), and kinked tails (J, left panel, gross image; right panel, radiograph) in pups born to ZIKV-infected dams.χ2 test (F), Spearman’s correlation analysis (G), and 1-way ANOVA with Bonferroni’s multiple comparisons test (A, C, and E). *P < 0.05.

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