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Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies.

ABSTRACT: Despite the detailed characterization of the inflammatory and endothelial changes observed in Sickle Cell Disease (SCD), the hierarchical relationship between elements involved in the pathogenesis of this complex disease is yet to be described. Meta-analyses of gene expression studies from public repositories represent a novel strategy, capable to identify key mediators in complex diseases. We performed several meta-analyses of gene expression studies involving SCD, including studies with patient samples, as well as in-vitro models of the disease. Meta-analyses were performed with the Inmex bioinformatics tool, based on the RankProd package, using raw gene expression data. Functional gene set analysis was performed using more than 60 gene-set libraries. Our results demonstrate that the well-characterized association between innate immunity, hemostasis, angiogenesis and heme metabolism with SCD is also consistently observed at the transcriptomic level, across independent studies. The enrichment of genes and pathways associated with innate immunity and damage repair-associated pathways supports the model of erythroid danger-associated molecular patterns (DAMPs) as key mediators of the pathogenesis of SCD. Our study also generated a novel database of candidate genes, pathways and transcription factors not previously associated with the pathogenesis of SCD that warrant further investigation in models and patients of SCD.

SUBMITTER: Hounkpe BW

PROVIDER: S-EPMC4673434 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies.

Hounkpe Bidossessi Wilfried BW Fiusa Maiara Marx Luz MM Colella Marina Pereira MP da Costa Loredana Nilkenes Gomes LN Benatti Rafaela de Oliveira Rde O Saad Sara T Olalla ST Costa Fernando Ferreira FF dos Santos Magnun Nueldo Nunes MN De Paula Erich Vinicius EV

Scientific reports 20151209

Despite the detailed characterization of the inflammatory and endothelial changes observed in Sickle Cell Disease (SCD), the hierarchical relationship between elements involved in the pathogenesis of this complex disease is yet to be described. Meta-analyses of gene expression studies from public repositories represent a novel strategy, capable to identify key mediators in complex diseases. We performed several meta-analyses of gene expression studies involving SCD, including studies with patien ...[more]

PMID: 26648000

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Project description:Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naïve infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naïve African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naïve children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.

Project description:To study basal resistance we inoculated tobacco plants with Pseudomonas syringae pv. syringae 61 hrcC mutants (gift of A. Collmer). To compare the expression profiles of basal resistance to hypersensitive response, we used P. syringae pv. syringae 61. Gene activation triggered by the live compatible pathogen P. syringae pv. tabaci was compared to kanamycine-inactivated P. tabaci (10 min in 100 ug/ml KM, then washed 2x in H2O). Water-infiltrated control leaves were used. The aim of another set of experiments was to investigate the influence of various signal transduction pathways on basal resistance. Control plants were infiltrated with P. syringae pv syringae hrcC mutant bacteria. These were compared to treatments, in which the bacterial suspensions were supplemented with inhibitors that can block a specific type of signal transduction pathway. The inhibitors represented Ca2+ signaling, lipid derived signals generated by phospholipase C and A, protein phosphorilation (kinases) and protein degradation (degradation of transcription repressors or activators). The used inhibitors were LaCl3, neomycin, aristolochic acid, K252a and MG115 respectively. 2-2.5 months old tobacco plants (Nicotiana tabacum cv. Samsun nn) were grown in a greenhouse in soil with cca. 16/8 hr light/dark period at 20°C, then in a growth chamber 2 days before and during experiments, under identical conditions. A syringe was used for the injection of bacteria or chemical solutions into the tobacco leaves. At 6 or 48 hours post inoculation, leaf samples were taken, and frozen in liquid nitrogen. Every experiment was carried out in 3 independent replicates. Total RNA was extracted using the Quiagen RNeasy Plant Mini kit and the Quiagen Rnase-free Dnase Set, then re-purified and concentrated on Microcon-30 (Millipore) columns. The concentration and quality of isolated RNA was estimated by measuring its absorbency at 260 and 280 nm and running on 1% agarose gel. Keywords: Direct comparison

Dataset Information

Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies.

Publications

Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies.

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