Accession Number : AD1018305


Title :   Metabolic Host Responses to Malarial Infection during the Intraerythrocytic Developmental Cycle


Descriptive Note : Journal Article


Corporate Author : ARMY MEDICAL RESEARCH AND MATERIEL COMMAND FORT DETRICK MD FORT DETRICK United States


Personal Author(s) : Wallqvist,Anders ; Fang,Xin ; Tewari,Shivendra G ; Ye,Ping ; Reifman,Jaques


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1018305.pdf


Report Date : 08 Aug 2016


Pagination or Media Count : 18


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-phosphatesecretion, 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.


Descriptors :   PARASITES , malaria , HOSTS (BIOLOGY) , BLOOD CELLS , gene expression , models , BIOMASS , metabolites , metabolism , STRESS(PHYSIOLOGY) , hemoglobin , interactions , inhibition


Distribution Statement : APPROVED FOR PUBLIC RELEASE