Histological chorioamnionitis shapes the neonatal transcriptomic immune response

Abstract

Background Histologic chorioamnionitis (HCA) is commonly associated with preterm birth and deleterious post-natal outcomes including sepsis and necrotizing enterocolitis. Transcriptomic analysis has been used to uncover gene signatures that permit diagnosis and prognostication, show new therapeutic targets, and reveal mechanisms that underlie differential outcomes with other complex disease states in neonates such as sepsis. Aims To define the transcriptomic and inflammatory protein response in peripheral blood among infants with exposure to histologic chorioamnionitis. Study Design Prospective, observational study. Subjects Uninfected preterm neonates retrospectively categorized based on placental pathology with no HCA exposure (n = 18) or HCA exposure (n = 15). Outcomes measures We measured the transcriptomic and inflammatory mediator response in prospectively collected whole blood. Results We found 488 significant (p<0.001), differentially expressed genes in whole blood samples among uninfected neonates with HCA exposure that collectively represented activated innate and adaptive immune cellular pathways and revealed a potential regulatory role for the pleotropic microRNA molecule miR-155. Differentially secreted plasma cytokines in patients with HCA exposure compared to patients without HCA included MCP-1, MPO, and MMP-9 (p < 0.05). Conclusions Exposure to HCA distinctively activates the neonatal immune system in utero with potentially long-term health consequences.

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

“…Next, we attempted to compare our cord blood data with human cord blood transcriptome modulated by CA but found no previous studies with raw DEG data. Instead, we found a recent study showing transcriptomic profile in newborn blood collected during the first 24 hours of life with 331 up and 157 downregulated genes related to innate and adaptive immune pathways in infants with vs without CA ( Supplemental Table S12), 14 relative to 258 and 10 genes, respectively, related mainly to innate immunity in our study ( Figure 4A). The magnitude of DEG regulation in our study (257/268 DEGs with fold change ≥2) was much greater than in the human study (449/488 DEGs with fold changes ≤1.5).…”

“…[11][12][13] Nevertheless, the mechanisms responsible for these modulations are unknown, although few studies showed activated innate immune status in the cord or newborn blood and blood hypo-responsiveness to in vitro bacterial challenge in infants with CA. [14][15][16][17] These results only reflected the fetal changes after CA but did not incorporate the impact of exogenous environmental exposure after birth (eg, bacteria, enteral feeding), which could further modify CA effects on neonatal immunity and sepsis risk. Further, empirical antibiotics are widely used right after CA-related preterm births to prevent EOS, partly due to poor sepsis diagnostics using blood culture.…”

In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes

“…Both share a close association with histological chorioamnionitis (HCA) 4–6 , an inflammation of the fetal membranes typically caused by intrauterine bacterial infection 7 . Fetal exposure to HCA induces in utero immune activation, resulting in fetal inflammatory response syndrome (FIRS), and shapes the neonatal transcriptomic immune response 8–10 . Clinical characteristics of FIRS consist of systemic inflammation and elevation of fetal plasma interleukin (IL)-6 and other pro-inflammatory cytokine levels 11 .…”

Chorioamnionitis exposure dampens the preterm monocyte response to subsequent challenges

“…Previous studies have utilized microarrays on umbilical cord blood of preterm infants exposed to chorioamnionitis and/or FIRS to evaluate the impact of this inflammatory exposure on the neonatal immune transcriptosome. They revealed that chorioamnionitis exposure altered the expression of genes important for antigen processing and presentation, innate, and adaptive immune responses and cellular metabolism . While these findings lay a nice foundation for the effect of chorioamnionitis on neonatal immune function, the methods used made it impossible to determine which cells were responsible for these findings and whether or not these alterations impacted the neonatal immune response to subsequent pathogens.…”

“…They revealed that chorioamnionitis exposure altered the expression of genes important for antigen processing and presentation, innate, and adaptive immune responses and cellular metabolism. 6,7 While these findings lay a nice foundation for the effect of chorioamnionitis on neonatal immune function, the methods used made it impossible to determine which cells were responsible for these findings and whether or not these alterations impacted the neonatal immune response to subsequent pathogens. The recent paper by de Jong et al addressed these deficiencies by performing RNA-seq on preterm umbilical cord blood purified monocytes with and without chorioamnionitis exposure both before and after stimulation with Staphylococcus epidermidis, the most common cause of neonatal late-onset sepsis.…”