Abstract
BackgroundThe malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically dependent on the infected human red blood cell (RBC). To describe whole cell metabolic activity within both P. falciparum and RBCs during the asexual reproduction phase of the intraerythrocytic developmental cycle, we developed an integrated host-parasite metabolic modeling framework driven by time-dependent gene expression data.ResultsWe validated the model by reproducing the experimentally determined 1) stage-specific production of biomass components and their precursors in the parasite and 2) metabolite concentration changes in the medium of P. falciparum-infected RBC cultures. The model allowed us to explore time- and strain-dependent P. falciparum metabolism and hypothesize how host cell metabolism alters in response to malarial infection. Specifically, the metabolic analysis showed that uninfected RBCs that coexist with infected cells in the same culture decrease their production of 2,3-bisphosphoglycerate, an oxygen-carrying regulator, reducing the ability of hemoglobin in these cells to release oxygen. Furthermore, in response to parasite-induced oxidative stress, infected RBCs downgraded their glycolytic flux by using the pentose phosphate pathway and secreting ribulose-5-phosphate. This mechanism links individually observed experimental phenomena, such as glycolytic inhibition and ribulose-5-phosphate secretion, to the oxidative stress response.ConclusionsAlthough the metabolic model does not incorporate regulatory mechanisms per se, alterations in gene expression levels caused by regulatory mechanisms are manifested in the model as altered metabolic states. This provides the model the capability to capture complex multicellular host-pathogen metabolic interactions of the infected RBC culture. The system-level analysis revealed complex relationships such as how the parasite can reduce oxygen release in uninfected cells in the presence of infected RBCs as well as the role of different metabolic pathways involved in the oxidative stress response of infected RBCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0291-2) contains supplementary material, which is available to authorized users.
Highlights
The malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically dependent on the infected human red blood cell (RBC)
The direct manipulation of fluxes allowed us to predict the metabolic host alterations for otherwise unknown molecular or regulatory interaction mechanisms. These analyses suggested that the oxygenreleasing capability of uninfected RBCs cocultured with P. falciparum-infected RBCs was decreased, providing a molecular mechanism that could contribute to hypoxia in malarial infection
By combining the metabolic network of the malarial parasite P. falciparum [15], the network of its host cells [17], and the parasite’s gene expression data during the intraerythrocytic developmental cycle (IDC) [18, 19], we developed an integrated host-parasite metabolic model that explicitly accounted for the metabolic activity within both P. falciparum and RBCs at each hour during the IDC
Summary
The malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically dependent on the infected human red blood cell (RBC). To describe whole cell metabolic activity within both P. falciparum and RBCs during the asexual reproduction phase of the intraerythrocytic developmental cycle, we developed an integrated host-parasite metabolic modeling framework driven by time-dependent gene expression data. The life cycle of P. falciparum includes a number of radically different host-dependent morphological stages [3]. It enters the human host through the bite of an infected Anopheles mosquito, where the infective sporozoites rapidly move to the liver and proliferate asymptomatically into merozoites. At around 30 h post-infection, the parasite enters the schizont stage, rapidly divides, and at ~48 h releases merozoites into the blood stream to complete the cycle
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