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Identification of distinct metabolic perturbations and associated immunomodulatory events during intra-erythrocytic development stage of pediatric Plasmodium falciparum malaria (part-III)

ABSTRACT: The goal of this study was to interrogate biochemical profiles manifested in human serum samples originating from a cohort of West African children, collected before and during P. falciparum malarial infection, with the aim of characterizing metabolic migration associated with severity of malarial infection.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

DISEASE(S): Malaria

SUBMITTER: Wael Abdrabou

PROVIDER: ST001517 | MetabolomicsWorkbench | Tue Aug 25 00:00:00 BST 2020

REPOSITORIES: MetabolomicsWorkbench

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Project description:We aimed at finding differently expressed genes in whole blood cells of African children with asymptomatic Plasmodium falciparum infection (A), uncomplicated malaria (U), severe malarial anemia (A) and cerebral malaria (Ce) compared one to another and to healthy children (Co). Understanding malarial immunopathology in the human host represents and enormous challenge for transcriptomic research. In this work, we used microarray and real-time RT-PCR technology to pursue deeper knowledge about the mechanisms underlying this disease in African children. To this end, we investigated the genomic transcriptional profiles in whole blood of healthy children and children with asymptomatic infection, uncomplicated malaria, malaria associated with severe anemia and cerebral malaria and compared them with previously published microarray results. We were able to discriminate between the different presentations of P. falciparum infection using supervised and unsupervised clustering of microarray data and unsupervised double-hierarchical clustering of real-time RT-PCR results of a set of 22 genes known to be expressed in at least one of the principal blood cell lineages. We further found considerable overlap between genes regulated in Kenyan and Gabonese children with symptomatic malaria, in contrast to adults with acute malaria from Cameroon. Different signatures for transcription factor binding sites in promoters of genes either up-regulated in symptomatic disease, specifically up-regulated in uncomplicated malaria or specifically down-regulated in cerebral malaria point out that similar gene expression in each of these clinical presentations is probably a result of common regulation at the transcriptional level. Immunoglobulin production, complement regulation and IFN beta signalling emerged as most discrepant features between uncomplicated malaria and all other investigated presentations, correlating with IRF7 and ISRE binding signatures in the corresponding genes. Down-regulation of several genes in cerebral malaria seems instead to be a response to hypoxia orchestrated by AhRF, GABP and HIF1 transcription factors. ARG1, BPI, CD163, IFI27, HP and TNFAIP6 transcript levels correlated positively with lactatemia and inversely with hemoglobin concentration and should be evaluated as prognostic markers to direct early therapeutic measures and prevent malarial disease evolution and death.

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Identification of distinct metabolic perturbations and associated immunomodulatory events during intra-erythrocytic development stage of pediatric Plasmodium falciparum malaria (part-III)

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