Using metabolomics to dissect host–parasite interactions

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Highlights

  • Metabolomic approaches have highlighted aspects of parasite metabolism essential for virulence.

  • Most mammalian infective parasite stages are dependent on sugars as primary carbon sources.

  • Key metabolic fluxes are regulated by metabolic rather than transcriptional mechanisms.

  • Significant differences in host and parasite central carbon metabolism offer opportunities for drug development.

Protozoan parasites have evolved diverse growth and metabolic strategies for surviving and proliferating within different extracellular and intracellular niches in their mammalian hosts. Metabolomic approaches, including high coverage metabolite profiling and 13C/2H-stable isotope labeling, are increasingly being used to identify parasite metabolic pathways that are important for survival and replication in vivo. These approaches are highlighting new links between parasite carbon metabolism and the ability of different parasite stages to colonize specific niches or host cell types. They have also revealed novel metabolic regulatory mechanisms that are important for homeostasis and survival in potentially nutrient variable environments. These studies highlight the importance of parasite and host metabolism as determinants of host–parasite interactions.

Section snippets

Background

Parasitic protozoa are an evolutionarily divergent group of unicellular eukaryotes that cause a range of important human and veterinary diseases. These pathogens often have complex life cycles, which can involve insect and mammalian hosts, as well as obligate intracellular and/or extracellular stages. While considerable progress has been made in identifying the molecular mechanisms that underlie parasite invasion of host cells and tissues and evasion of the host immune response, much less is

Studying parasite metabolism using metabolomics approaches

Analysis of intracellular metabolite pools from different parasite stages (profiling) or changes in extracellular metabolite levels during culture (footprinting) can be used to infer the operation of specific pathways and relative/absolute metabolic fluxes, respectively. Methods for rapidly quenching the metabolism of cultured parasite stages, parasite-infected host cells and isolated intracellular parasite stages have been developed [4, 5, 6••, 7, 8] as have methods for undertaking targeted or

Link between host cell range and parasite metabolic plasticity

Recent metabolomic studies on Toxoplasma gondii tachyzoite stages suggest that there is a strong link between the metabolic flexibility of intracellular parasite stages and their host range. T. gondii is one of the most successful parasites of humans, infecting nearly one third of the world's population, and other warm-blooded animals. Acute infections are caused by tachyzoite stages that can invade any nucleated cell and rapidly proliferate within a unique vacuolar compartment. Tachzyoites

Adapting a glycolytic metabolism to life in the blood

In contrast to T. gondii, a number of other parasites primarily or exclusively utilize glucose as their major carbon source and are completely dependent on glycolysis for energy generation. These include Plasmodium asexual red blood cell (RBC) stages and the T. brucei bloodstream forms (BSF) (Figure 1b,c). The dependence of these parasite stages on glucose uptake and glycolysis, with concomitant suppression of mitochondrial respiration [33, 35], likely represents an adaptation to the constant

Metabolic quiescence - an adaptive mechanism for avoiding activation of host cell anti-microbial responses?

Several obligate intracellular parasite stages enter a slow growth state and establish a silent infection with minimal activation of host cell antimicrobial responses or host cell death. This strategy is utilized by T. gondii bradyzoites [41], Plasmodium vivax hypnozoites [42] and Leishmania amastigotes [43], which reside within vacuolar compartments in neuronal and muscle cells, liver cells, and different phagocytic cells, respectively. It is often difficult (or impossible) to generate

Conclusions

Metabolomic approaches are beginning to highlight differences as well as common features of the central carbon metabolism in different parasite species and developmental stages that were not anticipated from genomic or transcriptomic studies. These studies suggest that, far from having an invariant, house-keeping function, parasite central carbon metabolism plays a key role in allowing these pathogens to adapt to different nutrient conditions and/or other stresses encountered in different host

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank all members of the McConville lab for discussions. MJM is an NHMRC Principal Research Fellow.

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