title: A Stem Cell Strategy Identifies Glycophorin C as a Major Erythrocyte Receptor for the Rodent Malaria Parasite Plasmodium berghei.
abstract: The clinical complications of malaria are caused by the parasite expansion in the blood. Invasion of erythrocytes is a complex process that depends on multiple receptor-ligand interactions. Identification of host receptors is paramount for fighting the disease as it could reveal new intervention targets, but the enucleated nature of erythrocytes makes genetic approaches impossible and many receptors remain unknown. Host-parasite interactions evolve rapidly and are therefore likely to be species-specific. As a results, understanding of invasion receptors outside the major human pathogen Plasmodium falciparum is very limited. Here we use mouse embryonic stem cells (mESCs) that can be genetically engineered and differentiated into erythrocytes to identify receptors for the rodent malaria parasite Plasmodium berghei. Two proteins previously implicated in human malaria infection: glycophorin C (GYPC) and Band-3 (Slc4a1) were deleted in mESCs to generate stable cell lines, which were differentiated towards erythropoiesis. In vitro infection assays revealed that while deletion of Band-3 has no effect, absence of GYPC results in a dramatic decrease in invasion, demonstrating the crucial role of this protein for P. berghei infection. This stem cell approach offers the possibility of targeting genes that may be essential and therefore difficult to disrupt in whole organisms and has the potential to be applied to a variety of parasites in diverse host cell types.
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Loukia
authors.initials: L
authors.lastname: Yiangou
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Ruddy
authors.initials: R
authors.lastname: Montandon
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Modrzynska
authors.affiliation: Mouse Developmental Genetics and ES Cells Mutagenesis, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Barry
authors.initials: B
authors.lastname: Rosen
authors.affiliation: Cellular Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bushell
authors.affiliation: Microbial Pathogenesis, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Alena
authors.identifier: http://orcid.org/0000-0002-9017-2644
authors.initials: A
authors.lastname: Pance
mesh_terms: D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000172:deficiency* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004920:Erythropoiesis; D006021:Glycophorins / Q000172:deficiency* / Q000378:metabolism; D006790:Host-Parasite Interactions; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000469:parasitology; D010962:Plasmodium berghei / Q000502:physiology*
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D006021:Glycophorins; C523515:Slc4a1 protein, mouse