Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug 8;10(1):58.
doi: 10.1186/s12918-016-0291-2.

Metabolic Host Responses to Malarial Infection During the Intraerythrocytic Developmental Cycle

Affiliations
Free PMC article

Metabolic Host Responses to Malarial Infection During the Intraerythrocytic Developmental Cycle

Anders Wallqvist et al. BMC Syst Biol. .
Free PMC article

Abstract

Background: 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.

Results: We 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.

Conclusions: Although 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.

Keywords: Gene expression data; Host-pathogen interactions; Intraerythrocytic developmental cycle; Metabolism; Oxidative stress response; Plasmodium falciparum.

Figures

Fig. 1
Fig. 1
Schematic description for calculating metabolic fluxes in Plasmodium falciparum and human red blood cells. a Uninfected and infected human red blood cell (RBC) cultures. We simulated metabolic activity within RBCs for two cell culture conditions, i.e., an uninfected culture that consists of normal RBCs and an infected culture consisting of P. falciparum-infected RBCs and cocultured uninfected RBCs. b Modeling framework. In order to describe metabolism in the infected cultured system, we used separate metabolic network descriptions for each RBC component. The P. falciparum model was imbedded in a separate compartment of the infected RBC, allowing metabolite uptake and secretion between these entities. Direct metabolite uptake and secretion with the medium was only possible for the infected and cocultured RBC model. c Workflow of flux calculations. We used experimental metabolomic data of the uninfected RBC culture [16] to determine normal and cocultured RBC fluxes using the RBC metabolic network. As for infected RBCs, we combined RBC and P. falciparum metabolic networks into one integrated network and incorporated the parasite’s gene expression data to predict both host RBC and P. falciparum metabolic fluxes. cRBC, cocultured uninfected RBCs; iRBC, P. falciparum-infected RBCs; nRBC, normal RBCs; MNPf, metabolic network of P. falciparum; MNRBC, metabolic network of RBC; NIC, number of internal compartments; NM, number of metabolites; NR, number of reactions; RPMI, Roswell Park Memorial Institute
Fig. 2
Fig. 2
Predicted overall biomass production rates μ and macromolecular syntheses of Plasmodium falciparum during the intraerythrocytic developmental cycle. a Rates for the HB3 (blue solid curve), 3D7 (green dashed curve), and Dd2 (red dotted curve) strains of P. falciparum at each hour during the intraerythrocytic developmental cycle are shown. The whole intraerythrocytic developmental cycle was classified into ring, trophozoite, and schizont stages [19]. μ values are expressed as gram biomass per hour per 1012 red blood cells (g/[h · 1012 RBC]). b Synthesized amounts of RNA, protein, DNA, and phospholipids in the HB3, 3D7, and Dd2 strains of P. falciparum in g/(h · 1012 RBC). Error bars represent standard deviation (N = 20) of model uncertainty induced in response to 10 % Gaussian noise added to the gene expression data (Additional file 1: Text S2)
Fig. 3
Fig. 3
Predicted time-dependent production of biomass metabolites for the HB3, 3D7, and Dd2 strains of Plasmodium falciparum. The heat map denotes the predicted time-dependent production levels of each biomass metabolite of P. falciparum, in which orange, grey, and blue colors represent high, normal, and low production levels, respectively. Based on the time-dependent production, we classified these metabolites into four groups. Groups I, II, and III include the metabolites mainly produced during the early (ring stage), middle (trophozoite and early schizont stages), and late (schizont stage) periods of the intraerythrocytic developmental cycle, respectively, whereas group IV includes the metabolites for which the production levels were basically constant throughout the intraerythrocytic developmental cycle. Production value of each individual metabolite is normalized with respect to the median of its value for the HB3 strain
Fig. 4
Fig. 4
Predicted energy production and consumption in three strains of Plasmodium falciparum. a Schematic description of energy production and consumption. Energy (in the form of ATP) was produced from glycolysis (black) and other metabolic pathways (green) and consumed by non-glycolytic metabolism (blue) and non-metabolic activity (grey). b-d: Predicted time-dependent ATP production and consumption with respect to metabolic and non-metabolic processes (excluding ATP used for RNA synthesis) in the HB3 (b), 3D7 (c), and Dd2 (d) strains. Production or consumption are expressed as mmol/(h · 1012 RBC). Error bars represent standard deviation (N = 20) of model uncertainty induced in response to 10 % Gaussian noise added to the gene expression data (Additional file 1: Text S2)
Fig. 5
Fig. 5
Extracellular metabolite concentrations for the Plasmodium falciparum 3D7-infected human red blood cell culture. Time-dependent computed (○) and experimental (●) concentrations of extracellular metabolites in the medium of the infected red blood cell (RBC) culture during the intraerythrocytic development cycle (IDC). Increasing values indicate secretion, whereas decreasing values indicate uptake. Note that the initial concentration values at t = 0 h are set to the experimental values and the model predicts the concentration changes for t ≠ 0 h. Error bars represent 95 % confidence interval calculated as ± 1.96 σ/√ N, where the standard deviation σ was determined from the data and N represent the number of replicates. We used N = 3 experimental biological replicates and N = 20 simulation results, which were derived by adding 10 % Gaussian noise to the gene expression data (Additional file 1: Text S2)
Fig. 6
Fig. 6
Extracellular amino acid concentrations for the Plasmodium falciparum 3D7-infected human red blood cell culture. Time-dependent computed (○) and experimental (●) concentrations of extracellular amino acids in the medium of the infected red blood cell (RBC) culture during the intraerythrocytic development cycle (IDC). Increasing values indicate secretion, whereas decreasing values indicate uptake. Note that the initial concentration values at t = 0 h are set to the experimental values and the model predicts the concentration changes for t ≠ 0 h. Error bars represent 95 % confidence interval calculated as ± 1.96 σ/√ N, where the standard deviation σ was determined from the data and N represents the number of replicates. We used N = 3 experimental biological replicates and N = 20 simulation results, which were derived by adding 10 % Gaussian noise to the gene expression data (Additional file 1: Text S2)
Fig. 7
Fig. 7
Flux ratios for reaction in the glycolysis pathways of human red blood cells. a The ratios of reaction fluxes in cocultured to those in normal red blood cells (RBCs). b Time-dependent ratios of reaction fluxes in infected RBCs to those in normal RBCs and time-dependent ATP transport from Plasmodium falciparum to its host RBC. ATP transport flux was expressed as mmol/(h∙1012 RBC). cRBCs, uninfected RBCs cocultured with iRBCs; DPGase, diphosphoglycerate phosphatase; DPGM, diphosphoglycero mutase; ENO, enolase; FBA, fructose bisphosphate aldolase; GAPD, glyceraldehyde-3-phosphate dehydrogenase; HEX, hexokinase; iRBCs, P. falciparum 3D7-infected RBCs in the infected RBC culture; LDH, lactate dehydrogenase; nRBCs, normal RBCs in the uninfected RBC culture; PFK, phosphofructokinase; PGI, glucose-6-phosphate isomerase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PYK, pyruvate kinase; TPI, triose-phosphate isomerase
Fig. 8
Fig. 8
The pathway used for oxidative stress alleviation in Plasmodium falciparum-infected human red blood cells. a The pathway used by P. falciparum-infected red blood cells (RBCs) to deal with oxidative stresses. b Metabolic fluxes through the reactions of GSHox, G6PD, and RU5Pt within infected and cocultured RBCs, i.e., uninfected RBCs cocultured with infected RBCs. c GSHox fluxes within G6PD-sufficient (wild type) and G6PD-deficient RBCs. cRBCs, un-infected RBCs co-cultured with iRBCs; G6PD, glucose 6-phosphate dehydrogenase; GSH, reduced glutathione; GSHox, the GSH-based oxidative stress alleviation; GSSG, oxidized glutathione; iRBCs, P. falciparum 3D7-infected RBCs in the infected RBC culture; RU5Pt, the transport of ribulose 5-phosphate from iRBCs into the medium

Similar articles

See all similar articles

Cited by 7 articles

See all "Cited by" articles

References

    1. World Health Organization. World Malaria Report 2014. WHO [online]. 2014. http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/.
    1. Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, Duffy PE. Malaria: progress, perils, and prospects for eradication. J Clin Invest. 2008;118(4):1266–76. doi: 10.1172/JCI33996. - DOI - PMC - PubMed
    1. Tuteja R. Malaria - an overview. FEBS J. 2007;274(18):4670–9. doi: 10.1111/j.1742-4658.2007.05997.x. - DOI - PubMed
    1. Cowman AF, Crabb BS. Invasion of red blood cells by malaria parasites. Cell. 2006;124(4):755–66. doi: 10.1016/j.cell.2006.02.006. - DOI - PubMed
    1. Mehta M, Sonawat HM, Sharma S. Glycolysis in plasmodium falciparum results in modulation of host enzyme activities. J Vector Borne Dis. 2006;43(3):95–103. - PubMed

Publication types

LinkOut - more resources

Feedback