Medical, Molecular and Forensic Sciences, Murdoch University, Perth, WA, Australia.
Division of the Institute of Reproductive and Developmental Biology, Imperial College Parturition Research Group, Imperial College London, London, United Kingdom.
PLoS One. 2020 Jun 1;15(6):e0233841. doi: 10.1371/journal.pone.0233841. eCollection 2020.
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.
由于复杂且动态的病理生理学以及在处理可用小体积血液方面的挑战，早产儿晚期脓毒症（LOS）期间宿主免疫反应的特征描述较差。我们在此介绍了对极早产儿 LOS 时外周全血进行的无偏转录组分析。
对胎龄<30 周的极早产儿外周血样本（生后 6-29 天）进行 RNA-Seq 分析，这些样本是在疑似 LOS 时采集的。根据血培养阳性和 C 反应蛋白浓度升高，将婴儿分为确诊 LOS（n=5）、可能 LOS（n=4）或无 LOS（n=9）。进行了生物信息学和统计分析，包括途径过度表达和蛋白质-蛋白质相互作用网络分析。进行了血浆细胞因子免疫测定以验证差异表达的细胞因子途径。
确诊 LOS 婴儿的血液白细胞转录反应与无 LOS 婴儿有显著差异（1317 个差异表达基因）。然而，可能 LOS 的婴儿不能与无 LOS 或确诊 LOS 的婴儿区分开来。与 LOS 相关的转录改变包括涉及病原体识别（主要是 TLR 途径）、细胞因子信号（促炎和抑制反应）、免疫和血液调节（包括细胞死亡途径）以及代谢（胆固醇生物合成改变）的基因。在 LOS 期间，转录水平的细胞因子反应的特征是 IFN-α/β、IFN-γ、IL-1 和 IL-6 信号通路的过度表达，以及炎症反应相关基因的上调。确诊 LOS 的婴儿其血浆中 IL-1α 和 IL-6 的水平明显更高。
LOS 极早产儿的血液反应表现为宿主免疫反应改变，这似乎反映了不平衡的免疫代谢稳态。
