Protective and Pathogenic Effects of Interferon Signaling During Pregnancy

Abstract

Immune regulation at the maternal-fetal interface is complex due to conflicting immunological objectives: protection of the fetus from maternal pathogens and prevention of immune-mediated rejection of the semiallogeneic fetus and placenta. Interferon (IFN) signaling plays an important role in restricting congenital infections as well as in the physiology of healthy pregnancies. In this review, we discuss the antiviral and pathogenic effects of type I IFN (IFN-α, IFN-β), type II IFN (IFN-γ), and type III IFN (IFN-λ) during pregnancy, with an emphasis on mouse and non-human primate models of congenital Zika virus infection. In the context of these animal model systems, we examine the role of IFN signaling during healthy pregnancy. Finally, we review mechanisms by which dysregulated type I IFN responses contribute to poor pregnancy outcomes in humans with autoimmune disease, including interferonopathies and systemic lupus erythematosus.

Keywords: Zika virus; interferons; pregnancy; systemic lupus erythematosus.

FIG. 1.

IFN signaling pathways. Type I, type II, and type III IFNs signal through distinct receptors, but activate overlapping transcriptional programs. More than a dozen type I IFNs, including IFN-α, IFN-β, IFN-ɛ, IFN-δ, and IFN-τ, signal through a heterodimeric receptor comprising IFNAR1 and IFNAR2. A smaller set of type III IFNs (IFN-λ) signal through a heterodimeric receptor comprising IFNLR1 and IL10Rb. The type II IFN family consists only of IFN-γ, which signals as a dimer through a tetrameric receptor comprising IFNGR1 and IFNGR2. Receptor binding activates kinases, including JAK1, JAK2, and TYK2, which phosphorylate STAT1 and STAT2. Phosphorylated STATs dimerize and translocate to the nucleus, where they activate transcription from promoters that contain ISRE (STAT1/2 heterodimers) or GAS (STAT1 homodimers), resulting in the expression of IFN-stimulated genes. The canonical IFN signaling pathways are depicted, but additional signaling pathways also are activated and likely contribute to the specific transcriptional response induced by different IFNs. GAS, γ-activated sites; IFN, interferon; ISRE, IFN-stimulated response elements. Color images are available online.