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Humboldt-Universitaet zu Berlin - Collaborative Research Center for Theoretical Biology

Membrane biogenesis modelling of a Toxoplasma gondii-infected human cell and deduction of underlying metabolic principles

Intracellular parasitism is a type of symbiotic relationship in which the parasite benefits from a prolonged and intimate association within its host cell. Intriguingly, the metabolic network of the obligate intracellular parasite Toxoplasma gondii harbors numerous biochemical pathways that are also present in its human host cell.

Toxoplasma has retained 800 metabolic reactions during its evolution, contributing to its robust intracellular parasitism and wide host specificity. For example, despite the discretionary access to host phospholipids and their precursors at minimal energy investment, the presence of endogenous membrane biogenesis in T. gondii is enigmatic. This redundancy of phospholipid biosynthesis present in T. gondii and its host cells allows us to investigate the fundamental principles that govern the metabolic design of an obligate intracellular parasite in the context of its host cell, and offers a novel perspective to pathogen–host interactions in general.

The proposed research intends to construct a kinetic model of the phospholipid homeostasis of a parasitized human cell in order to explain the preservation of de novo membrane biogenesis in T. gondii along with its strict auxotrophy regarding other key precursors of lipid synthesis. We hypothesize that during its natural evolution as an obligate and promiscuous intracellular parasite, T. gondii has attained an optimal trade-off in economizing its endogenous metabolic capacity while not imposing a too high metabolic burden on the host cell that might jeopardize its integrity. Hence, our premise rationalizes the evolutionary design of the metabolic networks in T. gondii as the outcome of an optimization process aimed at minimizing the parasite’s metabolism under the constraint that the host metabolism remains intact for a time period required for an efficient parasite reproduction. In order to establish evolutionary criteria, which upon optimization yields the observed network interrelations; we will apply methods of flux balance analysis. Though our model comprises only the phospholipid homeostasis of a T. gondii–infected human cell, it should be able to partially explain the evolution of T. gondii and other related obligate intracellular parasites of medical and veterinary importance, Plasmodium falciparum and Eimeria tenella.

This project aims to integrate the experimental and computational approaches to construct a kinetic model that represents the molecular interactions between the phospholipid syntheses of T. gondii and its host cell. Our initial working model is based on published and unpublished research together with the genome annotations of T. gondii and H. sapiens that will then be confirmed for its integrity through biochemical and genetic methods. For example, computer simulations of individual or multiple gene deletions in T. gondii would predict the resulting effect on phospholipid biogenesis and intracellular survival of the parasite. These predictions can be validated through gene-knockout experiments owing to amenability of T. gondii to genetic manipulation. This approach would also identify chemotherapeutic drug targets to disrupt the parasite membrane synthesis and, hence, its intracellular growth. Analysis of the interactive phospholipid networks of T. gondii and its host cell integrating the lipid biogenesis as well as the exchange of key precursors will be used to elucidate potential driving forces and constraints that for the first time provides a mathematical-experimental basis to understand the metabolic interrelationship of intracellular pathogens and their hosts.

german version