Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semi-allogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total PBMCs following delivery in healthy women were compared to those of non-pregnant control subjects. Interestingly, interferon stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14+ cells and could be stratified according to genetic variation at the interferon-3 gene (IFNL3, also named IL28B) single nucleotide polymorphism (SNP) rs12979860. Antiviral gene expression was sustained beyond six months following delivery in mothers with a CT or TT genotype but resembled baseline non-pregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together these data suggest that postpartum, the normalization of the physiological rheostat controlling interferon signaling is dependent on IFNL3 genotype.

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Price AA, Tedesco D, Prasad MR, Workowski KA, Walker CM, Suthar MS, Honegger JR, Grakoui A