title: Targeted disruption of a ring-infected erythrocyte surface antigen (RESA)-like export protein gene in Plasmodium falciparum confers stable chondroitin 4-sulfate cytoadherence capacity.
abstract: The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family proteins mediate the adherence of infected erythrocytes to microvascular endothelia of various organs, including the placenta, thereby contributing to cerebral, placental, and other severe malaria pathogenesis. Several parasite proteins, including KAHRP and PfEMP3, play important roles in the cytoadherence by mediating the clustering of PfEMP1 in rigid knoblike structures on the infected erythrocyte surface. The lack of a subtelomeric region of chromosome 2 that contains kahrp and pfemp3 causes reduced cytoadherence. In this study, microarray transcriptome analysis showed that the absence of a gene cluster, comprising kahrp, pfemp3, and four other genes, results in the loss of parasitized erythrocytes adhering to chondroitin 4-sulfate (C4S). The role of one of these genes, PF3D7_0201600/PFB0080c, which encodes PHISTb (Plasmodium helical interspersed subtelomeric b) domain-containing RESA-like protein 1 expressed on the infected erythrocyte surface, was investigated. Disruption of PFB0080c resulted in increased var2csa transcription and VAR2CSA surface expression, leading to higher C4S-binding capacity of infected erythrocytes. Further, PFB0080c-knock-out parasites stably maintained the C4S adherence through many generations of growth. Although the majority of PFB0080c-knock-out parasites bound to C4S even after culturing for 6 months, a minor population bound to both C4S and CD36. These results strongly suggest that the loss of PFB0080c markedly compromises the var gene switching process, leading to a marked reduction in the switching rate and additional PfEMP1 expression by a minor population of parasites. PFB0080c interacts with VAR2CSA and modulates knob-associated Hsp40 expression. Thus, PFB0080c may regulate VAR2CSA expression through these processes. Overall, we conclude that PFB0080c regulates PfEMP1 expression and the parasite's cytoadherence.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, suchigoel@gmail.com.
authors.forename: Suchi
authors.initials: S
authors.lastname: Goel
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Arivalagan
authors.initials: A
authors.lastname: Muthusamy
authors.affiliation: the Department of Entomology, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Jun
authors.initials: J
authors.lastname: Miao
authors.affiliation: the Department of Entomology, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Liwang
authors.initials: L
authors.lastname: Cui
authors.affiliation: the Centre for Medical Parasitology at the Department of International Health, Immunology, and Microbiology, Copenhagen University Hospital, DK 2014 Copenhagen, Denmark, and.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.affiliation: the Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California 92093.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, gowda@psu.edu.
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
mesh_terms: D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002809:Chondroitin Sulfates / Q000737:chemistry* / Q000378:metabolism; D002875:Chromosomes; D004912:Erythrocytes / Q000737:chemistry / Q000469:parasitology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D005810:Multigene Family; D010455:Peptides / Q000172:deficiency / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D018955:CD36 Antigens; C411566:EMP3 protein, Plasmodium falciparum; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D010455:Peptides; D015800:Protozoan Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C042968:knob protein, Plasmodium falciparum; D002809:Chondroitin Sulfates
keywords: Cell Adhesion; Cell Surface Protein; Chondroitin Sulfate; Glycosaminoglycan; Malaria; Parasite; Plasmodium