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Proceedings of the National Academy of Sciences
Article . 2019 . Peer-reviewed
License: CC BY
Data sources: Crossref
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PubMed Central
Other literature type . 2019
License: CC BY
Data sources: PubMed Central
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Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell

Authors: Mattie C. Pawlowic; Mastanbabu Somepalli; Adam Sateriale; Gillian T. Herbert; Alexis R. Gibson; Gregory D. Cuny; Lizbeth Hedstrom; +1 Authors

Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell

Abstract

The apicomplexan parasite Cryptosporidium is a leading global cause of severe diarrheal disease and an important contributor to early-childhood mortality. Waterborne outbreaks occur frequently, even in countries with advanced water treatment capabilities, and there is currently no fully effective treatment. Nucleotide pathways are attractive targets for antimicrobial development, and several laboratories are designing inhibitors of these enzymes as potential treatment for Cryptosporidium infections. Here we take advantage of newly available molecular genetics for Cryptosporidium parvum to investigate nucleotide biosynthesis by directed gene ablation. Surprisingly, we found that the parasite tolerates the loss of classical targets including dihydrofolate reductase-thymidylate synthase (DHFR-TS) and inosine monophosphate dehydrogenase (IMPDH). We show that thymidine kinase provides a route to thymidine monophosphate in the absence of DHFR-TS. In contrast, only a single pathway has been identified for C. parvum purine nucleotide salvage. Nonetheless, multiple enzymes in the purine pathway, as well as the adenosine transporter, can be ablated. The resulting mutants are viable under normal conditions but are hypersensitive to inhibition of purine nucleotide synthesis in their host cell. Cryptosporidium might use as-yet undiscovered purine transporters and salvage enzymes; however, genetic and pharmacological experiments led us to conclude that Cryptosporidium imports purine nucleotides from the host cell. The potential for ATP uptake from the host has significant impact on our understanding of parasite energy metabolism given that Cryptosporidium lacks oxidative phosphorylation and glycolytic enzymes are not constitutively expressed throughout the parasite life cycle.

Country
United Kingdom
Keywords

Diarrhea, 570, Cryptosporidium, 610, Cryptosporidiosis, name=General, IMP Dehydrogenase, Multienzyme Complexes, Cell Line, Tumor, /dk/atira/pure/subjectarea/asjc/1000, Humans, Purine, Cryptosporidium parvum, Nucleotides, Biological Transport, Thymidylate Synthase, Biological Sciences, Parasite, Tetrahydrofolate Dehydrogenase, Purines, Nucleotide

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
65
Top 1%
Top 10%
Top 10%
Green
hybrid