Maternal Interferon Lambda Signaling Limits Transplacental Transmission And Mediates Fetal Pathology During Congenital Zika Virus Infection In Mice
JOURNAL OF IMMUNOLOGY(2020)
摘要
Abstract Zika virus (ZIKV) is among the few pathogens that can surmount the physical and immune barriers of the maternal-fetal interface to cause congenital infections. Immunity at the maternal-fetal interface is carefully balanced to protect the developing fetus from maternal immune rejection as well as maternal pathogens, and includes cytokines secreted by the placenta. Interferon lambda (IFN-λ) is secreted constitutively from human placental trophoblasts, and limits ZIKV transplacental transmission in mouse congenital infection models. To determine if IFN-λ is secreted from mouse placentas, we evaluated IFN-λ activity from placentas of mid-gestation and laboring dams. IFN-λ activity was present in infected and laboring placentas, but not in uninfected mid-gestation placentas, suggesting that IFN-λ is not constitutively secreted from mouse placentas. To define the tissues that respond to IFN-λ at the maternal-fetal interface, we assessed ZIKV transplacental transmission in mouse pregnancies in which either fetal or maternal tissues lacked the IFN-λ receptor (Ifnlr1−/−). Unexpectedly, the antiviral effects of IFN-λ resulted exclusively from signaling in maternal tissues, as fetal viral loads depended only on maternal Ifnlr1 genotype, not the fetal/placental genotype. Using mice also lacking the type I IFN receptor, we studied the effect of IFN-λ signaling in pregnancies with enhanced ZIKV replication and again found an antiviral effect of maternal IFN-λ signaling. Pregnancies with maternal IFN-λ signaling also exhibited enhanced fetal pathology, suggesting that IFN-λ signaling can contribute to fetal pathology in high-viremia models.
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关键词
congenital zika virus infection,maternal interferon lambda,transplacental transmission,fetal pathology
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