Severe malaria due to Plasmodium falciparum infection remains a serious threat to health worldwide and new therapeutic targets are highly desirable. Small molecule inhibitors of prenyl transferases, enzymes that catalyze the post-translational isoprenyl modifications of proteins, exhibit potent antimalarial activity. The antimalarial actions of prenyltransferase inhibitors indicate that protein prenylation is required for malaria parasite development. In this study, we used a chemical biology strategy to experimentally characterize the entire complement of prenylated proteins in the human malaria parasite. In contrast to the expansive mammalian and fungal prenylomes, we find that P. falciparum possesses a restricted set of prenylated proteins. The prenylome of P. falciparum is dominated by Rab GTPases, in addition to a small number of prenylated proteins that also appear to function primarily in membrane trafficking. Overall, we found robust experimental evidence for a total of only thirteen prenylated proteins in P. falciparum, with suggestive evidence for an additional two probable prenyltransferase substrates. Our work contributes to an increasingly complete picture of essential, post-translational hydrophobic modifications in blood-stage P. falciparum.

Current evidence suggests that malarial infection could alter metabolites in the breath of patients, a phenomenon that could be exploited to create a breath-based diagnostic test. However, no study has explored this in a clinical setting. To investigate whether natural human malarial infection leads to a characteristic breath profile, we performed a field study in Malawi. Breath volatiles from children with and those without uncomplicated falciparum malaria were analyzed by thermal desorption-gas chromatography/mass spectrometry. Using an unbiased, correlation-based analysis, we found that children with malaria have a distinct shift in overall breath composition. Highly accurate classification of infection status was achieved with a suite of 6 compounds. In addition, we found that infection correlates with significantly higher breath levels of 2 mosquito-attractant terpenes, α-pinene and 3-carene. These findings attest to the viability of breath analysis for malaria diagnosis, identify candidate biomarkers, and identify plausible chemical mediators for increased mosquito attraction to patients infected with malaria parasites.

The malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid organelle that possesses plant-like metabolic pathways. Plants use the plastidial isoprenoid biosynthesis pathway to produce volatile odorants, known as terpenes. In this work, we describe the volatile chemical profile of cultured malaria parasites. Among the identified compounds are several plant-like terpenes and terpene derivatives, including known mosquito attractants. We establish the molecular identity of the odorant receptors of the malaria mosquito vector Anopheles gambiae, which responds to these compounds. The malaria parasite produces volatile signals that are recognized by mosquitoes and may thereby mediate host attraction and facilitate transmission.

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In this report, we present a post hoc analysis from two observational cohorts, comparing the global breath volatile profile captured when using polymer sampling bags (mixed breath) versus Bio-VOC™ (alveolar breath).