Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

Abstract

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic 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 peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant 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-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant 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 IFN signaling depends on IFNL3 genotype. postpartum | CD14 | interferon | innate immunity | antiviral genes

Interferon Lambda: Modulating Immunity in Infectious Diseases

“…This minor allele genotype of rs12979860 (TT) has also been associated with a higher and prolonged ISG expression in HCV infection (79,80,87,90,103,111). Interestingly, the same SNP of the IFNL3 gene is associated with a higher ISG expression in mothers after childbirth, suggesting that postpartum the normalization of physiological control of IFN signaling depends on the IFNL3 genotype (112). Although the rs12979860 SNPs have been specifically associated with IFNL3/ L4 expression, these SNPs might also affect the expression of the other IFN-λ genes (80,87,113).…”

Type III Interferons in Hepatitis C Virus Infection

“…It is postulated that the innate immune system will play a significant role against pathogens, while the adaptive immune responses are dampened by increased Tregs activity (89, 90). Another recent study showed that the expression of innate immunity genes is enriched in postpartum women compared to control (91). Interestingly, ISGs level in women of the CT or TT IFN-λ3 rs12979860 genotype remained elevated as late as 24 weeks after childbirth, while women with the CC IFN-λ3 genotype were comparable to non-pregnant controls (91).…”

“…Another recent study showed that the expression of innate immunity genes is enriched in postpartum women compared to control (91). Interestingly, ISGs level in women of the CT or TT IFN-λ3 rs12979860 genotype remained elevated as late as 24 weeks after childbirth, while women with the CC IFN-λ3 genotype were comparable to non-pregnant controls (91). This reflects what was observed in the context of acute HCV where individuals with non-favorable CT or TT IFN-λ3 genotype had a higher baseline ISG expression in the liver.…”

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

“…Growing literature demonstrates genetic associations between rs368234815 or its linked variants with other clinical phenotypes, such as relapse on DAA treatment of HCV (12), liver fibrosis (13, 14), hepatic metallothionein expression (15), post-partum immune activation (16, 17), risk of mucinous ovarian cancer (18), etc. Although other, invariantly expressed type-III IFNs might be also important for these phenotypes, only IFN-λ4 is directly and most dramatically affected by the associated variant, rs368234815, that either creates or eliminates IFN-λ4.…”