Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

Raman, Sainath; Klein, Nigel; Kwan, Antonia; Hubank, Mike; Rahman, Shamima; Rashid, Asrar; Peters, Mark

doi:10.1007/s00134-015-3817-y

Cited by 5 publications

(6 citation statements)

References 6 publications

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“…However, the letter does not report the clinical outcomes of the patients investigated. The findings from our and previous gene expression studies are consistent with a long held view that mitochondrial dysfunction and altered oxidative phosphorylation have implications in sepsis pathophysiology [ 46 , 47 ]—a theme that has recently received renewed attention [ 44 , 48 , 49 ]. In the context of meningococcal sepsis, the intense down-regulation of genes associated with oxidative phosphorylation indicates that N. meningitidis as part of a pro-inflammatory response may induce dysfunction of oxidative phosphorylation and deranged energy metabolism [ 50 , 51 ]—which has also been referred to as “cytopathic hypoxia” [ 52 ]—which contributes to rapidly evolving multiple organ failure.…”

Section: Discussionsupporting

confidence: 89%

“…Wong et al used IPA and identified that genes up-regulated in neutrophils from sepsis patients enriched pathways related to mitochondrial dysfunction [ 40 ]. Two more recent studies have more specifically studied the differential regulation of genes associated with oxidative phosphorylation in sepsis patients [ 44 , 45 ]. One study by Weiss et al [ 45 ] determined the differential expression of 296 nuclear-encoded mitochondrial genes in whole blood collected within 24 h of admission from pediatric patients with septic shock compared with non-septic controls.…”

Section: Discussionmentioning

confidence: 99%

“…They also identified that a sub-group of patients with higher rate of multiple-organ failure and higher mortality rate had a greater repression of nuclear-encoded mitochondrial genes, compared with two other sub-groups. Another smaller study, reported in a letter to the editor by Raman et al [ 44 ] describes gene expression in whole-blood in previously healthy children with meningococcal septicemia at 0, 4, 8, 12, 24, and 48 h from time of admission. They identified an immediate reduction of gene expression associated with oxidative phosphorylation processes, and it continued to decrease over the 48 h, leading the authors to suggest that mitochondrial dysfunction contributed to multi-organ failure.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic data from two primary cell models stimulating human monocytes suggest inhibition of oxidative phosphorylation and mitochondrial function by N. meningitidis which is partially up-regulated by IL-10

et al. 2017

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BackgroundBiological interpretation of DNA microarray data may differ depending on underlying assumptions and statistical tests of bioinformatics tools used. We used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to analyze previously generated DNA microarray data from human monocytes stimulated with N. meningitidis and IL-10 (“the model system”), and with meningococcal sepsis plasma before and after immunodepletion of IL-10 (“the patient plasma system”). The objectives were to compare if the two bioinformatics methods resulted in similar biological interpretation of the datasets, and to identify whether GSEA provided additional insight compared with IPA about the monocyte host response to meningococcal activation.ResultsIn both experimental models, GSEA and IPA identified genes associated with pro-inflammatory innate immune activation, including TNF-signaling, Toll-like receptor signaling, JAK-STAT-signaling, and type I and type II interferon signaling. GSEA identified genes regulated by the presence of IL-10 with similar gene sets in both the model system and the patient plasma system. In the model system, GSEA and IPA in sum identified 170 genes associated with oxidative phosphorylation/mitochondrial function to be down-regulated in monocytes stimulated with meningococci. In the patient plasma system, GSEA and IPA in sum identified 122 genes associated with oxidative phosphorylation/mitochondrial dysfunction to be down-regulated by meningococcal sepsis plasma depleted for IL-10. Using IPA, we identified IL-10 to up-regulate 18 genes associated with oxidative phosphorylation/mitochondrial function that were down-regulated by N. meningitidis.ConclusionsBiological processes associated with the gene expression changes in the model system of meningococcal sepsis were comparable with the results found in the patient plasma system. By combining GSEA with IPA, we discovered an inhibitory effect of N. meningitidis on genes associated with mitochondrial function and oxidative phosphorylation, and that IL-10 partially reverses this strong inhibitory effect, thereby identifying, to our knowledge, yet another group of genes where IL-10 regulates the effect of LPS. We suggest that relying on a single bioinformatics tool together with an arbitrarily chosen filtering criteria for data analysis may result in overlooking relevant biological processes and signaling pathways associated with genes differentially expressed between compared experimental conditions.Electronic supplementary materialThe online version of this article (10.1186/s12865-017-0229-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transcriptomic data from two primary cell models stimulating human monocytes suggest inhibition of oxidative phosphorylation and mitochondrial function by N. meningitidis which is partially up-regulated by IL-10

et al. 2017

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“…Gene set expression analysis is a method allowing the comparison of multiple gene sets or pathways and was used by Raman et al (38) on the Kwan dataset to show a temporal fall in oxidative phosphorylation GE. Our study also used GSEA applied to the polymicrobial dataset, using controls as a comparison, to A displays GE analysis according to the cell type in the Emonts dataset, specifically for TNF, NFKB1, VEGF-A, and VEGF-B genes, with controls removed and gene symbols collapsed.…”

Section: Discussionmentioning

confidence: 99%

A Transcriptomic Appreciation of Childhood Meningococcal and Polymicrobial Sepsis from a Pro-inflammatory and Trajectorial Perspective, a Role for VEGF-A and VEGF-B Modulation?

Rashid¹,

Brusletto

Al-Obeidat

et al. 2023

Shock

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This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression (GE) changes associated with pro-inflammatory processes. Five datasets, including four meningococcal sepsis shock (MSS) datasets (two temporal and two longitudinal) and one polymicrobial sepsis dataset, were selected to track temporal changes in gene expression. Hierarchical clustering revealed three temporal phases: early, intermediate, and late, providing a framework for understanding sepsis progression. Principal Component Analysis (PCA) plots supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent up-regulation of VEGF-A and NFKB1, genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the post-mortem dataset comparing MSS cases to controls, VEGF-A was up-regulated and VEGF-B down-regulated. Renal tissue exhibited higher VEGF-A expression compared to other tissues. Similar VEGF-A upregulation and VEGF-B downregulation patterns were observed in the cross-sectional MSS datasets and the polymicrobial sepsis dataset. Hexagonal plots confirmed VEGFR-VEGFR2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day three and sepsis day three samples compared to controls. These findings provide insights into the dynamic nature of sepsis from a transcriptomic perspective, suggesting potential implications for biomarker development. Future research should focus on larger-scale temporal transcriptomic studies with appropriate control groups and validate the identified gene combination as a potential biomarker panel for sepsis.

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“…Overall, 16 studies containing 17 different cohorts were included (Table 1a-b). These 16 studies include expression profiles from both adult 13,15,17,[26][27][28][29][30][31][32][33][34][35] and pediatric 31,[36][37][38][39] cohorts. In these cases, the gene expression data were publicly available.…”

Section: Systematic Searchmentioning

confidence: 99%

Mortality prediction in sepsis via gene expression analysis: a community approach

Henao

et al. 2016

Preprint

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Improved risk stratification and prognosis in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here three scientific groups were invited to independently generate prognostic models for 30-day mortality using 12 discovery cohorts (N=650) containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance was validated in 5 cohorts of community-onset sepsis patients (N=189) in which the models showed summary AUROCs ranging from 0.765-0.89. Similar performance was observed in 4 cohorts of hospital-acquired sepsis (N=282). Combining the new gene-expression-based prognostic models with prior clinical severity scores led to significant improvement in prediction of 30-day mortality (p<0.01). These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis, improving both resource allocation and prognostic enrichment in clinical trials.

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Oxidative phosphorylation gene expression falls at onset and throughout the development of meningococcal sepsis-induced multi-organ failure in children

Cited by 5 publications

References 6 publications

Transcriptomic data from two primary cell models stimulating human monocytes suggest inhibition of oxidative phosphorylation and mitochondrial function by N. meningitidis which is partially up-regulated by IL-10

Transcriptomic data from two primary cell models stimulating human monocytes suggest inhibition of oxidative phosphorylation and mitochondrial function by N. meningitidis which is partially up-regulated by IL-10

A Transcriptomic Appreciation of Childhood Meningococcal and Polymicrobial Sepsis from a Pro-inflammatory and Trajectorial Perspective, a Role for VEGF-A and VEGF-B Modulation?

Mortality prediction in sepsis via gene expression analysis: a community approach

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