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Prolonged Activation of Innate Antiviral Gene Signature After Childbirth Is Determined by IFNL3 Genotype

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Prolonged Activation of Innate Antiviral Gene Signature After Childbirth Is Determined by IFNL3 Genotype Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype Aryn A. Pricea,b, Dana Tedescoa,b, Mona R. Prasadc, Kimberly A. Workowskid, Christopher M. Walkere,f, Mehul S. Suthara,b,g, Jonathan R. Honeggere,f,1, and Arash Grakouia,b,h,1 aEmory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329; bYerkes National Primate Research Center, Emory University, Atlanta, GA 30329; cDepartment of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, OH 43205; dDepartment of Medicine, Emory University School of Medicine, Atlanta, GA 30322; eThe Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205; fDepartment of Pediatrics, The Ohio State University School of Medicine, Columbus, OH, 43205; gDepartment of Pediatrics and Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; and hDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329 Edited by Michael B. A. Oldstone, The Scripps Research Institute, La Jolla, CA, and approved July 26, 2016 (received for review February 11, 2016) Maternal innate and adaptive immune responses are modulated IFN-γ production (15). We hypothesized that maternal innate during pregnancy to concurrently defend against infection and immune activation extends beyond gestation, thus compensating tolerate the semiallogeneic fetus. The restoration of these systems for the lag phase in postpartum T-cell immunity. We tested this after childbirth is poorly understood. We reasoned that enhanced hypothesis by comparing the transcriptional profiles of total pe- innate immune activation may extend beyond gestation while ripheral blood mononuclear cells (PBMCs) from healthy mothers adaptive immunity recovers. To test this hypothesis, the transcrip- following delivery in relation to nonpregnant control subjects tional profiles of total peripheral blood mononuclear cells follow- (NPCs). We identified an IFN-stimulated gene (ISG) signature that + ing delivery in healthy women were compared with those of was primarily expressed in CD14 cells and depended on the in- nonpregnant control subjects. Interestingly, interferon-stimulated terferon-λ3(IFNL3, also known as IL28B) single-nucleotide poly- genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as morphism (SNP) rs12979860. Together these data suggest that well as signaling proteins such as STAT1, STAT2, and MAVS, were IFNL3 genotype may influence innate immunity following delivery. enriched postpartum. Antiviral genes were primarily expressed in + CD14 cells and could be stratified according to genetic variation at Results λ IFNL3 the interferon- 3 gene ( , also named IL28B) SNP rs12979860. We used a systems biology approach to identify gene expression Antiviral gene expression was sustained beyond 6 mo following patterns and pathways that may contribute to postpartum control delivery in mothers with a CT or TT genotype, but resembled base- of viral infections. PBMCs were collected 2 wk following delivery line nonpregnant control levels following delivery in mothers with from two healthy mothers, UM07 and UM08, and two NPCs, a CC genotype. CT and TT IFNL3 genotypes have been associated NPC354 and NPC357. All NPC subjects were women in their with persistent elevated ISG expression in individuals chronically in- fected with hepatitis C virus. Together, these data suggest that post- childbearing years who had never been pregnant. Postpartum partum, the normalization of the physiological rheostat controlling genes enriched at least twofold over NPCs were included in the IFN signaling depends on IFNL3 genotype. analysis; 982 genes were differentially expressed in both UM07 and UM08. Further analysis of these genes by DAVID bio- postpartum | CD14 | interferon | innate immunity | antiviral genes informatics indicated that the top five enriched biological processes were related to immune response [Gene Ontology (GO):0006955], positive regulation of defense response to virus aternal immunoregulatory adaptations such as the expan- sion of regulatory T cells (T ) with potent immunosup- by host (GO:0002230), response to virus (GO:0009615), defense M regs response to virus by host (GO:0050691), and regulation of immune pressive capacity serve to maintain fetal tolerance during pregnancy A (1, 2). Although tolerance mechanisms are necessary for fetal effector process (GO:0002697) (Fig. 1 ). Remarkably, all five survival, suppressed cellular immunity renders pregnant women susceptible to severe infection with certain pathogens (3–7). Significance Augmented innate immunity may partially offset the reduced adaptive immune protection in pregnancy (8, 9). Following de- In this study, we examined the possibility that the maternal livery, however, the maternal immune system is released from innate immune system is modulated following delivery. We the constraints of pregnancy. identified an interferon-stimulated gene signature that was The postpartum period is associated with alterations in the primarily expressed in CD14+ cells circulating in the peripheral severity of certain autoimmune diseases and enhanced control of blood. Postpartum antiviral gene expression depended on the several chronic viruses. For example, multiple sclerosis symptom interferon-λ3(IFNL3) single-nucleotide polymorphism rs12979860, severity is often alleviated during pregnancy and exacerbated which suggests that IFNL3 genotype may influence a mother’s following delivery (10). Similarly, women persistently infected innate immune response following delivery. with hepatitis C virus (HCV) or hepatitis B virus (HBV) may experience a precipitous decrease in viral load in the months Author contributions: A.A.P., D.T., C.M.W., M.S.S., J.R.H., and A.G. designed research; A.A.P., – D.T., M.S.S., and J.R.H. performed research; A.A.P., D.T., C.M.W., M.S.S., J.R.H., and A.G. following delivery (11 13). Factors that contribute to the enhanced analyzed data; A.A.P., D.T., C.M.W., M.S.S., J.R.H., and A.G. wrote the paper; and M.R.P. postpartum viral control are not fully understood, although in the and K.A.W. recruited subjects. context of HCV infection, the decrease in viral load was linked in The authors declare no conflict of interest. two women to the emergence of viral variants with escape mu- This article is a PNAS Direct Submission. tations in class I epitopes, suggesting a restoration of virus-spe- + Data deposition: The data reported in this paper have been deposited in the Gene Ex- cific CD8 T-cell selection pressure (11). pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE85960). There is evidence, however, that a brief lag phase in T-cell 1To whom correspondence may be addressed. Email: jonathan.honegger@nationwidechildrens. function may occur following delivery. Although absolute num- org or [email protected]. bers of T cells normalize by 1-mo postpartum (14, 15), these T This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. cells may possess functional effector deficits such as decreased 1073/pnas.1602319113/-/DCSupplemental. 10678–10683 | PNAS | September 20, 2016 | vol. 113 | no. 38 www.pnas.org/cgi/doi/10.1073/pnas.1602319113 Downloaded by guest on September 27, 2021 biological processes were associated with immunity, and three of NPCs (Fig. 1C). Interestingly, many antiviral genes were enriched as these were specifically related to antiviral immunity. late as 24 wk following delivery. Expression patterns varied from Due to the number of antiviral genes within the “defense re- transient expression 2- to 4-wk postpartum, as in the case of MAVS sponse to virus” biological process, this category was investigated and STAT2, to prolonged expression from 12 to 24 wk following further. The enriched antiviral defense genes encoded proteins delivery, as exemplified by IFIT1, IFIT2,andIFIT3 (Fig. 1C). with antiviral effector function (IFIT1, IFIT2, IFIT3, and OAS1) IFIT1, IFIT2, IFIT3,andOAS1 were chosen for further analysis and signaling function (STAT1, STAT2, MAVS, and TLR7). because of their relative fold increases in transcript levels within total Interestingly, the IFN-α/β signaling pathway was enriched post- PBMCs. These genes are canonical ISGs that when translated pos- partum. Network analysis identified STAT1 and STAT2 to be sess antiviral function against numerous viruses. The IFN-induced the regulatory nodes within the network (Fig. 1B). STAT1 and protein with tetratricopeptide repeats (IFIT) family proteins func- STAT2 are key modulators of type I and type III IFN signaling, tion by inhibiting distinct steps of the viral life cycle (16), whereas oligoadenylate synthetase 1 (OAS1) activates RNase L to cleave and together these data are consistent with up-regulated antiviral viral RNA (17). Because the transcriptome analysis indicated that IFN signaling in peripheral blood cells following delivery in IFIT1, IFIT2, IFIT3,andOAS1 remained elevated 6-mo postpartum UM07 and UM08. in PBMCs from UM07 and UM08, we extended these findings in We then examined the duration of antiviral gene enrichment additional healthy mothers. PBMCs were collected from 10 mothers following delivery. Gene expression analysis was performed on at late time points following delivery (Table S1). RT-PCR was used PBMCs from UM07 and UM08 obtained 2-, 4-, 12-, and 24-wk to compare transcript expression
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