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Breathprinting Reveals Malaria-Associated Biomarkers and Mosquito Attractants

ABSTRACT: Current evidence suggests that malaria infection could alter patient breath metabolites, a phenomenon that could be exploited to create a breath-based diagnostic test. Indications include the preferential attraction of the Anopheles mosquito vector upon infection and a distinct breath profile with the progression of experimental, sub-microscopic malaria. However, these observations have yet to be extended to the clinic. To investigate whether natural human malaria infection leads to a characteristic breath profile, we performed a field study in Malawi. Breath volatiles from pediatric patients with and without uncomplicated falciparum malaria were analyzed by thermal desorption-gas chromatography/mass spectrometry. Using an unbiased, correlation-based analysis, we find that children with malaria have a distinct shift in overall breath composition. Leveraging these differences, highly accurate classification of infection status was achieved with a suite of six compounds. In addition, we find that malaria-infected children have significantly higher breath levels of two mosquito-attractant terpenes, α-pinene and 3-carene. Thus, our work attests to the viability of breath analysis for malaria diagnosis, identifies candidate compounds for follow-up studies, and identifies biologically plausible chemical mediators for increased mosquito attraction to malaria-infected patients.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Breath

SUBMITTER: Chad Schaber

PROVIDER: ST000883 | MetabolomicsWorkbench | Sun Oct 08 00:00:00 BST 2017

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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Breathprinting Reveals Malaria-Associated Biomarkers and Mosquito Attractants

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