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Whole-blood transcriptional signatures composed of erythropoietic and Nrf2-regulated genes differ between cerebral malaria and severe malarial anemia

ABSTRACT: We compared genome-wide transcription profiles of whole blood obtained from Ugandan children with acute CM (n=17) or SMA (n=17) and community children without Plasmodium falciparum infection (n=12) and determined the relationships between gene expression, hematological indices, and relevant plasma biomarkers. Results demonstrated both CM and SMA predominantly upregulated enrichment of dendritic cell (DC), inflammatory/TLR/chemokines, monocyte, and antigen presentation modules but downregulated enrichment of lymphocyte modules. Neurodegenerative disease pathways showed modest upregulation during CM. Nrf2-regulated genes were over-expressed in children with SMA compared to CM, especially those with HbSS, corresponding with increased plasma heme oxygenase-1. Reticulocyte-specific gene expression was markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/IRF2 module expression and plasma IP-10/CXCL10 negatively correlated with reticulocyte-specific signatures. This study concludes that, compared to SMA, CM is associated with downregulation of Nrf2-related and reticulocyte-specific signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117613 | GEO | 2018/07/28

REPOSITORIES: GEO

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Whole-blood transcriptional signatures composed of erythropoietic and Nrf2-regulated genes differ between cerebral malaria and severe malarial anemia

Project description:Whole-blood transcriptional signatures composed of erythropoietic and Nrf2-regulated genes differ between cerebral malaria and severe malarial anemia

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Whole-Blood Transcriptional Signatures Composed of Erythropoietic and NRF2-Regulated Genes Differ Between Cerebral Malaria and Severe Malarial Anemia.

Project description:BackgroundAmong the severe malaria syndromes, severe malarial anemia (SMA) is the most common, whereas cerebral malaria (CM) is the most lethal. However, the mechanisms that lead to CM and SMA are unclear.MethodsWe compared transcriptomic profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without Plasmodium falciparum infection (n = 12) and determined the relationships among gene expression, hematological indices, and relevant plasma biomarkers.ResultsBoth CM and SMA demonstrated predominantly upregulated enrichment of dendritic cell activation, inflammatory/Toll-like receptor/chemokines, and monocyte modules, but downregulated enrichment of lymphocyte modules. Nuclear factor, erythroid 2 like 2 (Nrf2)-regulated genes were overexpressed in children with SMA relative to CM, with the highest expression in children with both SMA and sickle cell disease (HbSS), corresponding with elevated plasma heme oxygenase-1 in this group. Erythroid and reticulocyte-specific signatures were markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/interferon-regulatory factor 2 module expression and plasma interferon-inducible protein-10/CXCL10 negatively correlated with reticulocyte-specific signatures.ConclusionsCompared with SMA, CM is associated with downregulation of Nrf2-related and erythropoiesis signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.

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