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

ABSTRACT: Host immune responses during late-onset sepsis (LOS) in very preterm infants are poorly characterised due to a complex and dynamic pathophysiology and challenges in working with small available blood volumes. We present here an unbiased transcriptomic analysis of whole peripheral blood from very preterm infants at the time of LOS. RNA-Seq was performed on peripheral blood samples (6 – 29 days postnatal age) taken at the time of suspected LOS from very preterm infants <30 weeks gestational age. Infants were classified based on blood culture positivity and elevated C-reactive protein concentrations as having confirmed LOS (n=5), possible LOS (n=4) or no LOS (n=9). Bioinformatics and statistical analyses performed included pathway over-representation and protein-protein interaction network analyses. Plasma cytokine immunoassays were performed to validate differentially expressed cytokine pathways.The blood leukocyte transcriptional responses of infants with confirmed LOS differed significantly from infants without LOS (1,317 differentially expressed genes). However, infants with possible LOS could not be distinguished from infants with no LOS or confirmed LOS. Transcriptional alterations associated with LOS included genes involved in pathogen recognition (mainly TLR pathways), cytokine signalling (both pro-inflammatory and inhibitory responses), immune and haematological regulation (including cell death pathways), and metabolism (altered cholesterol biosynthesis). At the transcriptional-level cytokine responses during LOS were characterised by over-representation of IFN-α/β, IFN-γ, IL-1 and IL-6 signalling pathways and up-regulation of genes for inflammatory responses. Infants with confirmed LOS had significantly higher levels of IL-1α and IL-6 in their plasma. Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138712 | GEO | 2020/06/03

REPOSITORIES: GEO

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Project description:Acquired neonatal brain lesions result from the co-incidence of environment deleterious factors occurring at a specific development stage. Hypoxia-ischemia and inflammation are the major triggers of brain damage in late pregnancy and early infancy, and result in a variety of damages depending on whether it affected fetuses, early or late preterm infants or at term neonates. Indeed brain responses to insults are different depending on age, since cerebral tissue presents a rapidly evolving cellular and biochemical substrate in this period. Clearly age-dependent etiology is largely documented; e.g. Intraventricular/intraparenchymal (IVH/IPH) brain hemorrhage in fetuses and extreme preterm (less than 28 gestation weeks; GW); focal or diffuse periventricular leucomalacia in preterm aged 28-34 GW or cortical necrosis in term infants. Definite periods of occurrence of preterm-encephalopathy are associated to particular vulnerability of distinct cell populations. Functional deficits remain in grown-up and represent a human and economical burden. IVH/IPH affects extreme preterm infants. It specific periventricular germinal matrix (GM) localization reveal vascular vulnerability at this site during a definite period. GM is the site of particularly intense metabolism due to neural cell precursor multiplication and angiogenesis. In addition, GM is at risk of hypoperfusion or perfusion arrest due to its watershed situation between centripetal and centrifugal vascular supplies, especially in very preterm infants otherwise subjected to fluctuant hemodynamics. Thus vascular bed in GM cumulates hypoxia-ischemia risks. The vulnerability of vasculature in this area was referred to be linked to intense angiogenesis and micro-vessels remodeling. Indeed endothelial support by pericytes and astrocytes end-feet is loose in these vessels and angiogenic factors also exhibit pro-hemorrhage potential. The blood to brain interface referred to as neurovascular unit is the multicellular structure shaping endothelial cells to regulate vascular permeability. The blood brain barrier (BBB) restrains pericellular diffusion and allows specific trans-endothelial transports. In previous studies in mice, we have observed structural and functional differences between young and adult brain microvascular endothelial cells (mvEC). Of note mvEC from neonates express the NMDA receptor and glutamate in these cells elicit protease secretions involved in vascular remodeling, while adult mvEC did not. Genetic inactivation of the t-PA inhibitor-1 allowed to mimick an age dependent IVH/IPH up to 5 days post-natal (P5) in mice. These observations (and others) support the hypothesis that mouse brain microvessels represent a heuristic paradigm in the study of vascular maturity as a favoring background for age dependent neonate brain hemorrhage. The present project was designed at studying constitutive protein contents of brain microvessels in a large scale, around the period of high disruption propensity (P5). We prepared enriched fractions of mouse forebrain microvessels (fMV) in order to insolating the neurovascular unit made of endothelial cells linked by blood brain barrier junctions, basal lamina including pericytes, astrocyte and neuritic end-feet from P5 (pro-hemorrhagic state), P10 (Immature hemorrhage resistant state) and P60 (Mature) mice, to study proteome onotogeny in fMV.

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

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