Metabolic signatures of Besnoitia besnoiti-infected endothelial host cells and blockage of key metabolic pathways indicate high glycolytic and glutaminolytic needs of the parasite

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• 作者：A. Taubert ; C. Hermosilla ; L. M. R. Silva ; A. Wieck ; K. Failing…
• 刊名：Parasitology Research
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：115
• 期：5
• 页码：2023-2034
• 全文大小：1,699 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Medical Microbiology
  Microbiology
  Immunology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1955
• 卷排序：115

文摘

Besnoitia besnoiti is an obligate intracellular and emerging coccidian parasite of cattle with a significant economic impact on cattle industry. During acute infection, fast-proliferating tachyzoites are continuously formed mainly in endothelial host cells of infected animals. Given that offspring formation is a highly energy and cell building block demanding process, the parasite needs to exploit host cellular metabolism to meet its metabolic demands. Here, we analyzed the metabolic signatures of B. besnoiti-infected endothelial host cells and aimed to influence parasite proliferation by inhibitors of specific metabolic pathways. The following inhibitors were tested: fluoro 2-deoxy-d-glucose and 2-deoxy-d-glucose (FDG, DG; inhibitors of glycolysis), 6-diazo-5-oxo-l-norleucin (DON; inhibitor of glutaminolysis), dichloroacetate (DCA; inhibitor of pyruvate dehydrogenase kinase which favorites channeling of glucose carbons into the TCA cycle) and adenosine-monophosphate (AMP; inhibitor of ribose 5-P synthesis). Overall, B. besnoiti infections of bovine endothelial cells induced a significant and infection rate-dependent increase of glucose, lactate, glutamine, glutamate, pyruvate, alanine, and serine conversion rates which together indicate a parasite-triggered up-regulation of glycolysis and glutaminolysis. Thus, addition of DON, FDG, and DG into the cultivation medium of B. besnoiti infected endothelial cells led to a dose-dependent inhibition of parasite replication (4 μM DON, 99.5 % inhibition; 2 mM FDG, 99.1 % inhibition; 2 mM DG, 93 % inhibition; and 8 mM DCA, 71.9 % inhibition). In contrast, AMP had no significant effects on total tachyzoite production up to a concentration of 20 mM. Together, these data may open new strategies for the development of therapeutics for B. besnoiti infections.KeywordsCoccidiaMetabolic signatureGlycolysisGlutaminolysisDON2-Deoxy-d-glucose