Gene expression profiling at birth characterizing the preterm infant with early onset infection

Abstract

Early onset infection (EOI) in preterm infants <32 weeks gestational age (GA) is associated with a high mortality rate and the development of severe acute and long-term complications. The pathophysiology of EOI is not fully understood and clinical and laboratory signs of early onset infections in this patient cohort are often not conclusive. Thus, the aim of this study was to identify signatures characterizing preterm infants with EOI by using genome-wide gene expression (GWGE) analyses from umbilical arterial blood of preterm infants. This prospective cohort study was conducted in preterm infants <32 weeks GA. GWGE analyses using CodeLink human microarrays were performed from umbilical arterial blood of preterm infants with and without EOI. GWGE analyses revealed differential expression of 292 genes in preterm infants with EOI as compared to infants without EOI. Infants with EOI could be further differentiated into two subclasses and were distinguished by the magnitude of the expression of genes involved in both neutrophil and T cell activation. A hallmark activity for both subclasses of EOI was a common suppression of genes involved in natural killer (NK) cell function, which was independent from NK cell numbers. Significant results were recapitulated in an independent validation cohort. Gene expression profiling may enable early and more precise diagnosis of EOI in preterm infants.Key message Gene expression (GE) profiling at birth characterizes preterm infants with EOI.GE analysis indicates dysregulation of NK cell activity.NK cell activity at birth may be a useful marker to improve early diagnosis of EOI. Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-016-1466-4) contains supplementary material, which is available to authorized users.

Whole blood transcriptional responses of very preterm infants during late-onset sepsis

“…We also found over-representation of the oxygen-dependent proline HIF1A pathway and up-regulation of HIF1A (transcription factor HIF1α) [91]. Our findings were consistent with studies showing significant overexpression of HIF1A during EOS in preterm infants (<32 weeks gestation) [92] and during bacterial sepsis in very preterm infants [16]. The induction of HIF1α in response to sepsis-associated cytopathic hypoxia has also been shown in previous human adult and mouse sepsis studies [33,[93][94][95][96].…”

Comparative Analysis of Global Gene Expression and Complement Components Levels in Umbilical Cord Blood from Preterm and Term Neonates: Implications for Significant Downregulation of Immune Response Pathways related to Prematurity

“…This might be attributed to different ethnic groups tested, as in our study all neonates were Caucasian, whereas in the study by Vora et al both African American and non-Hispanic Whites infants were included. Nevertheless, our results regarding downregulation of genes involved in immune/inflammatory signalling function in preterm infants compared with term infants are in concordance with previously discussed study by Vora et al and other reports 47 , 48 . In a recent meta-analysis, when eight various foeto-maternal tissue types were analysed separately, only UCB showed significant differentially expressed genes and those UCB samples that came from PTB showed downregulation in several innate immune-related pathways when compared with term samples 47 .…”

<p>Neonatal sepsis biomarkers: where are we now?</p>

“…A study that employed genome-wide expression analysis on blood samples from both infected and healthy preterm infants revealed differential regulation of 292 genes, many of which were involved in either neutrophil function or T-cell activation. 78 Differential expression of genes regulating natural killer-cell function was found to be present, indicating that this may be an interesting future target for research. 78 Using surface-enhanced laser desorption/ionization timeof-flight mass spectrometry (MS) on cord-blood samples, one group of investigators were able to identify a precocious haptoglobin "switch-on" pattern (Hp&HpRp) that allowed for development of a "mass restricted score" for the diagnosis of EOS.…”

“…78 Differential expression of genes regulating natural killer-cell function was found to be present, indicating that this may be an interesting future target for research. 78 Using surface-enhanced laser desorption/ionization timeof-flight mass spectrometry (MS) on cord-blood samples, one group of investigators were able to identify a precocious haptoglobin "switch-on" pattern (Hp&HpRp) that allowed for development of a "mass restricted score" for the diagnosis of EOS. 79 The significance of the Hp&HpRp pattern was evaluated in a prospective cohort of 174 preterm newborns, and by combining this result with IL6 levels and hematological indices, investigators were able to identify infants who were most at risk of EOS.…”