Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites

Srivastava, Anubhav, Creek, Darren J., Evans, Krystal J., De Souza, David, Schofield, Louis, Müller, Sylke, Barrett, Michael P., McConville, Malcolm J., and Waters, Andrew P. (2015) Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites. PLoS Pathogens, 11 (6). e1004882. pp. 1-22.

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Abstract

Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5'-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites.

Item ID: 42055
Item Type: Article (Research - C1)
ISSN: 1553-7374
Additional Information:

© 2015 Srivastava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funders: Wellcome Trust (WT), National Health and Medical Research Council (NHMRC), European Virtual Institute of Malaria Research (EVIMR), University of Glasgow (UoG)
Projects and Grants: WT grant 083811/Z/ 07/Z, NHMRC grant 1059530, EVIMR grant FP7-PEOPLE-2010-IRSES Project 5, UoG Staff Research Scholarship 2009-14
Date Deposited: 08 Dec 2015 18:07
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 60%
11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified @ 40%
SEO Codes: 92 HEALTH > 9299 Other Health > 929999 Health not elsewhere classified @ 100%
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