Humboldt-Universität zu Berlin - Molekulare Parasitologie

Metabolismus und Wirt-Parasit Interaktion

Nishith Gupta
Dr. Nishith Gupta

Tel.:    +49 30 2093-6404

Fax:    +49 30 2093-6041


Article: Parasite-host interactions

Intracellular Parasitism

Parasitism is a non-mutual relationship between two different organisms where a parasite lives at the expense of its host instead of seeking out its own resources. Particularly relevant and interesting parasites include intracellular pathogens, which co-opt individual host cells and utilize their cellular machinery to acquire the necessary resources. Obligate intracellular parasites infect a wide range of hosts, including both wild and domesticated animals and also humans. Infection can either be asymptomatic or elicit trivial symptoms, and it is often the case that those infected are unaware of their newly acquired parasites – indeed, remaining undetected is a viable strategy for a parasite and underlies its evolutionary success. In many cases, however, parasites produce debilitating symptoms, which can lead to fatality. There is a sizeable yearly socioeconomic burden attributable to parasites. It is therefore imperative to build a complete understanding of how they survive and reproduce in order to develop treatments and to improve the lives of those affected by parasitic infections.


Parasites of interest

Our aim is to identify the interplay between pathogen and host metabolism to better understand the concept of obligate intracellular parasitism. In particular, we study three different parasite genera of the protozoan phylum, Toxoplasma, Plasmodium and Eimeria. Toxoplasma gondii is considered to be one of the most successful pathogens on Earth due to its infective diversity, and is found in nearly all warm-blooded vertebrates. About one-quarter of the world’s population is seropositive to this parasite. The parasite infection is generally asymptomatic or produces mild flu-like symptoms, but in immuno-suppressed individuals, such as those affected by HIV/ AIDS and ageing, or patients undergoing organ transplants, it can lead to cerebral and ocular toxoplasmosis and eventual death. It also causes spontaneous abortion during pregnancy, and cognitive defects in newborns. Eimeria species inflict gastrointestinal diarrhea (Coccidiosis) in a variety of animals including poultry. Plasmodium is the culprit parasite responsible for malaria, which kills about 1 million people annually.


What can we learn from metabolism?

A successful parasite must be able to access the host cell’s resources and allocate them towards its own cellular demands, which vary depending on the parasite’s phase. This requires a crosstalk between the metabolic networks of the parasite and host cell. Through study of how they interact, and how parasites deal with changes in host cell metabolism, one can learn how to manipulate them and develop strategies to inhibit parasite growth. Our work explores the functioning of intertwined host-parasite networks in parasitized cells. Moreover, our group is studying metabolic transformation and network interactions occurring when a parasite switches between its replicative and non-replicative stages. Some parasites, such as Toxoplasma are highly promiscuous, meaning that they are able to infect a multitude of different vertebrate hosts and survive in virtually any nucleated cell. This contrasts with Plasmodium and Eimeria species, which are highly host-specific parasites. Through the course of evolution, these parasites have gained or lost metabolic pathways, optimizing their life cycles with that of their host cell. For example, Toxoplasma, Plasmodium and Eimeria express about 400-700 metabolic enzymes. When compared to a typical mammalian cell expressing ≈1400 enzymes, the data implies multiple metabolic dependencies of these parasites as well as their unique adaptation to parasitism. Our lab strives to clarify the relationship between the parasites’ metabolic capacities and their ability to infect different hosts. If appropriate metabolites are not available in a host, then the parasite will not be able to survive and reproduce in that particular environment. This could provide clues as to how the aforementioned parasites are adapted specifically to different hosts and tissues, and may suggest new drug targets.


Initial findings and their impact

We have already made significant progress in our research endeavors. For example, we have identified and characterized several metabolic enzymes required for parasite growth. In particular, our team has demonstrated that disrupted synthesis of certain membrane lipids arrests Toxoplasma reproduction and decreases parasite-induced host cell lysis. These findings could therefore have important implications in designing novel therapeutics. Further, we have discovered key metabolic strategies of apicomplexan parasites. Of particular note is the investigation and comparison of sugar metabolism in Toxoplasma and Plasmodium. We have shown a divergence in their carbon usage, with Toxoplasma demonstrating an unprecedented level of nutrient flexibility, which perhaps underlies its comparatively much wider host range. Additionally, Toxoplasma has also been shown to have a greater plasticity in its membrane biogenesis that parallels to a free-living metazoan cell. Such a versatile and autonomous sugar and lipid metabolism might ensure the survival and growth of Toxoplasma in a variety of nutritional milieus encountered in different host cells. Our engagement with Eimeria has also identified several host factors regulating parasite development. This work shows how this parasite subverts the immune and metabolic pathways of its mouse host to promote its own life cycle. Last but not least, similarities have also emerged between the metabolic functioning of replicating parasites and cancer cells, which has the potential to bridge the fields of parasitology and tumor biology.