title: Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites.
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.
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom; Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom.
authors.forename: Anubhav
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom; Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Division of Infection and Immunity, Parkville, Victoria, Australia.
authors.forename: Krystal J
authors.initials: KJ
authors.lastname: Evans
authors.affiliation: Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: De Souza
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Division of Infection and Immunity, Parkville, Victoria, Australia; Australian Institute of Tropical Health and Medicine, Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Townsville, Australia.
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
authors.affiliation: Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom.
authors.forename: Sylke
authors.initials: S
authors.lastname: Müller
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom; Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.affiliation: Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom; Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Waters
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D051379:Mice; D051381:Rats; D012156:Reticulocytes / Q000378:metabolism* / Q000469:parasitology*