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Gene expression signatures identify pediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

ABSTRACT: Multiple organ dysfunction syndrome (MODS) can result from a variety of initiating events such as infection or trauma. The clinical condition of some MODS patients may deteriorate and require intense resource and high-risk cardiopulmonary support via extracorporeal membrane oxygenation (ECMO). Until now, no diagnostic criteria/molecular biomarker has been developed to identify MODS patients who require subsequent ECMO support. We used multi-time point (0h, 72h and 8d) whole transcriptomics from total blood of 27 patients (contro-4, MODS-17 and ECMO-6) to derived the molecular signatures to diagnose the MODS patients required ECMO support. We observed that immune response (neutrophil level) was compromised in MODS patients, who required ECMO support. Differential gene expression analysis and gene ontology enrichment has revealed that epigenetic modifications has got activated during the MODS deterioration to ECMO. In addition, signature of 6 genes were identified using logistic regression, which can be used as putative diagnostic markers for patients needed ECMO support.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144406 | GEO | 2020/09/30

REPOSITORIES: GEO

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Project description:Metabolically quiescent pathogens can persist in a viable non-replicating state for months or even years. In specific infectious diseases, such as tuberculosis, cryptococcosis, histoplasmosis, latent infection is a corollary of this dormant state, with at some point a phase of reactivation, leading to the symptoms of the infection. During murine cryptococcosis and macrophage uptake, stress and host immunity induce C. neoformans heterogeneity with generation of a sub-population of yeasts that has been shown to harbor a phenotype compatible with dormancy (low stress response, latency of growth). In this subpopulation, mitochondrial transcriptional activity has been shown to be up regulated and this phenotype has been considered as a hallmark of quiescence in stem cells. Based on these findings, we worked to reproduce this phenotype in vitro model and standardized the experimental conditions to generate dormancy in Cryptococcus neoformans. We found that incubation of stationary phase yeasts (STAT) in nutriment limited conditions and hypoxia during 8 days (8D-HYPOx) were able to mimic the phenotype obtained in vivo. In these conditions, mortality and/or apoptosis occurred in less than 5% of the yeasts compared to 30-40% of apoptotic or dead yeasts upon incubation in normoxia (8D-NORMOx). Yeasts in 8D-HYPOx harbored a lower stress response, delayed growth and less that 1% of culturability on agar plates, suggesting that these yeasts are viable but non culturable cells (VBNC). These VBNC were able to reactivate in the presence of pantothenic acid, a vitamin that is known to be involved in quorum sensing and precursor of acetyl-CoA. Global metabolism of 8D-HYPOx cells showed some specific requirements and was globally shut down compared to 8D-NORMOx and STAT conditions. Mitochondrial analyses showed that the mitochondrial masse increased with mitochondria mostly depolarized in 8D-HYPOx compared to 8D-NORMox with an increased expression of mitochondrial genes. Proteomic and transcriptomic analyses of 8D-HYPOx revealed that the number of secreted proteins and transcripts detected also decreased compared to 8D-NORMOx and STAT, but proteome, secretome and transcriptome harbored specific profiles that are engaged as soon as four days of incubation. Importantly, acetyl-CoA and fatty acid pathway involving mitochondria is required for the generation and viability maintenance of VBNC. All together, these data show that we were able to generate for the first time VBNC phenotype in Cryptococcocus neoformans. This VBNC state is associated with a reduced and specific metabolism that should be further studied to understand dormancy/quiescence in this organism.

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Gene expression signatures identify pediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

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