Srinivas Nallandhighal1, Gregory S Park2, Yen-Yi Ho3, Robert O Opoka4, Chandy C John1,2,5, Tuan M Tran1,5. 1. Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis. 2. Division of Global Pediatrics, Department of Pediatrics, University of Minnesota Medical School, Minneapolis. 3. Department of Statistics, College of Arts and Sciences, University of South Carolina, Columbia. 4. Department of Paediatrics and Child Health, Makerere University, Kampala, Uganda. 5. Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis.
Abstract
Background: Among 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. Methods: We 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. Results: Both 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. Conclusions: Compared 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.
Background: Among 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. Methods: We 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. Results: Both 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. Conclusions: Compared 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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