Mining the Human Host Metabolome Toward an Improved Understanding of Malaria Transmission

Abstract

The big data movement has led to major advances in our ability to assess vast and complex datasets related to the host and parasite during malaria infection. While host and parasite genomics and transcriptomics are often the focus of many computational efforts in malaria research, metabolomics represents another big data type that has great promise for aiding our understanding of complex host-parasite interactions that lead to the transmission of malaria. Recent analyses of the complement of metabolites present in human blood, skin and breath suggest that host metabolites play a critical role in the transmission cycle of malaria. Volatile compounds released through breath and skin serve as attractants to mosquitoes, with malaria-infected hosts appearing to have unique profiles that further increase host attractiveness. Inside the host, fluctuations in the levels of certain metabolites in blood may trigger increased production of transmission-competent sexual stages (gametocytes), setting the stage for enhanced transmission of malaria from human to mosquito. Together, these recent discoveries suggest that metabolites of human blood, skin and breath play critical roles in malaria transmission. This review discusses recent advances in this area, with a focus on metabolites that have been identified to play a role in malaria transmission and methods that may lead to an improved understanding of malaria transmission.

Comparative Analysis of Host Metabolic Alterations in Murine Malaria Models with Uncomplicated or Severe Malaria

“…Blood-stage malaria causes hemolysis of both infected and noninfected erythrocytes, leading to the release of hemoglobin and heme to the serum. ,, Heme oxygenase-1 (HO-1) antagonizes heme’s toxic effects by converting heme into biliverdin (green pigment), carbon monoxide, and iron. , Biliverdin in turn gets reduced to bilirubin (orange pigment) by biliverdin reductase . The increased biliverdin and bilirubin levels observed in our study affirm hemolysis and hepatic dysfunction, as have also been reported for human malaria infections. ,,− …”

Insights into malaria pathogenesis gained from host metabolomics

“…Sphingolipid metabolism has been thought to play a role in signaling related to immune responses and vascular integrity and possibly aid in controlling the infection [37]. Aside from bloodstream changes, enriched levels of certain VOCs have also been detected in the skin odor of humans with asymptomatic P. falciparum malaria, including ethylbenzene, which has been shown to be a mosquito attractant [8,38].…”

“…These metabolome studies have both confirmed previous biological findings that were determined through careful molecular and cellular experimental work as well as shed light on new findings for which the biological underpinnings are still unclear. Prior reviews have provided an overview of the metabolism of Plasmodium from a host–parasite interaction viewpoint [ 6 , 7 ] as well as covering how host metabolites may contribute to malaria transmission [ 8 ]. Here, this review aims to summarize the status of our knowledge about metabolic fluctuations that occur in the host during malaria infection that may relate to malaria pathogenesis, immunity, and diagnosis.…”

“…Aside from bloodstream changes, enriched levels of certain VOCs have also been detected in the skin odor of humans with asymptomatic P . falciparum malaria, including ethylbenzene, which has been shown to be a mosquito attractant [ 8 , 38 ].…”

Enhanced Attraction of Arthropod Vectors to Infected Vertebrates: A Review of Empirical Evidence

“…Emami et al (2017) have shown that a metabolite produced by Plasmodium falciparum ((E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; HMBPP) induces red blood cells to produce molecules involved in mosquito attraction (CO 2 , aldehydes, and monoterpenes). The mechanisms involved in these potential parasite-induced phenotypic alteration (Poulin, 1995) are yet not all identified and several unknowns remain to be discovered (Busula et al, 2017b;Joice Cordy, 2020).…”