Document Type

Article

Department

Paediatrics and Child Health (East Africa)

Abstract

Background: Plasmodium falciparum malaria can rapidly progress to severe disease that can lead to death if left untreated. Severe malaria cases commonly present as severe malarial anemia (SMA), defined in children as hemoglobin (Hb) <5 g/dL with parasitemia, or as cerebral malaria (CM), which manifests as parasitemia with acute neurological deficits and has an inpatient mortality rate of ~20%. The molecular and cellular processes that lead to CM and SMA are unclear.

Methods: In a cross-sectional study, 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 P. falciparum infection (n = 12) who were enrolled in a parent cohort study of severe malaria. We determined the relationships between gene expression, hematological indices, and plasma biomarkers, including inflammatory cytokines.

Results: Both CM and SMA demonstrated enrichment of dendritic cell activation, inflammatory/TLR/chemokines, monocyte, and neutrophil modules but depletion of lymphocyte modules. Neurodegenerative disease and neuroinflammation pathways were enriched in CM. Increased Nrf2 pathway gene expression corresponded with increased plasma heme oxygenase-1 and the heme catabolite bilirubin in a manner specific to children with both SMA and sickle cell disease. Reticulocyte-specific gene expression was markedly decreased in CM relative to SMA despite higher Hb levels and appropriate increases in plasma erythropoietin. Viral sensing/interferon regulatory factor (IRF) 2 module (M111) expression and plasma IP-10 levels both negatively correlated with reticulocyte-specific signatures, but only M111 expression independently predicted decreased reticulocyte-specific gene expression after controlling for leukocyte count, Hb level, parasitemia, and clinical syndrome by multiple regression.

Conclusion: Differences in the blood transcriptome of CM and SMA relate to neurologically relevant pathways and erythropoiesis. Erythropoietic suppression during severe malaria is more pronounced during CM versus SMA and is positively associated with IRF2 blood signatures. Future studies are needed to validate these findings.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Open forum infectious diseases

DOI

https://doi.org/10.1093/ofid/ofy209.079

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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