Widespread functional specialization of Plasmodium falciparum erythrocyte membrane protein 1 family members to bind CD36 analysed across a parasite genome

Plasmodium falciparum ‐infected erythrocytes sequester from blood circulation by binding host endothelium. A large family of variant proteins mediates cytoadherence and their binding specificity determines parasite sequestration patterns and potential for disease. The aim of the present study was to understand how binding properties are encoded into family members and to develop sequence algorithms for predicting binding. To accomplish these goals computational approaches and a binding assay were used to characterize adhesion across Plasmodium falciparum erythrocyte membrane 1 (PfEMP1) proteins in the 3D7 parasite genome. We report that most family members encode the capacity to bind CD36 in the protein's semi‐conserved head structure and describe the sequence characteristics of a group of PfEMP1 proteins that do not. Structural and functional grouping of PfEMP1 proteins based upon head structure and additional domain architectural properties provide new insights into the protein family. These can be used to investigate the role of proteins in malaria pathogenesis and potentially tailor vaccines to recognize particular binding variants.

[1]  P. Kubes,et al.  Visualization of Plasmodium falciparum–Endothelium Interactions in Human Microvasculature , 2000, The Journal of experimental medicine.

[2]  A. Cowman,et al.  The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Steketee,et al.  The problem of malaria and malaria control in pregnancy in sub-Saharan Africa. , 1996, The American journal of tropical medicine and hygiene.

[4]  M. Molyneux,et al.  Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. , 1999, The Journal of infectious diseases.

[5]  R. Leke,et al.  Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum-infected erythrocytes that protect against placental parasitemia. , 2001, The Journal of infectious diseases.

[6]  B. Gamain,et al.  Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. , 2000, Molecular and biochemical parasitology.

[7]  A. Pain,et al.  Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells , 1999, Nature.

[8]  Jonathan E. Allen,et al.  Genome sequence of the human malaria parasite Plasmodium falciparum , 2002, Nature.

[9]  M. Wahlgren,et al.  Role of Nonimmune IgG Bound to PfEMP1 in Placental Malaria , 2001, Science.

[10]  François Nosten,et al.  Maternal antibodies block malaria , 1998, Nature.

[11]  S. Kyes,et al.  A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. , 2000, Molecular and biochemical parasitology.

[12]  M. Molyneux,et al.  Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria , 2000, Nature Medicine.

[13]  B. Gamain,et al.  Decoding the language of var genes and Plasmodium falciparum sequestration. , 2001, Trends in parasitology.

[14]  Tomoaki Tamaki,et al.  Sequence of Plasmodium falciparum chromosome 12 , 2002, Nature.

[15]  Z Bian,et al.  Antigenic variation and cytoadherence of PfEMP1 of Plasmodium falciparum-infected erythrocyte from malaria patients. , 2000, Chinese medical journal.

[16]  B. Gamain,et al.  Definition of the minimal domain of CIDR1alpha of Plasmodium falciparum PfEMP1 for binding CD36. , 2002, Molecular and biochemical parasitology.

[17]  H. Webster,et al.  Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. , 1991, The Journal of infectious diseases.

[18]  J. Reeder,et al.  Identification of Glycosaminoglycan Binding Domains in Plasmodium falciparum Erythrocyte Membrane Protein 1 of a Chondroitin Sulfate A-Adherent Parasite , 2000, Infection and Immunity.

[19]  H. Singh,et al.  Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequence. , 1997, Blood.

[20]  A. Pain,et al.  Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Cowman,et al.  clag9: A cytoadherence gene in Plasmodium falciparum essential for binding of parasitized erythrocytes to CD36. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  E V Koonin,et al.  Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. , 1998, Science.

[23]  A. Pain,et al.  A non-sense mutation in Cd36 gene is associated with protection from severe malaria , 2001, The Lancet.

[24]  M. Fried,et al.  Two DBLgamma subtypes are commonly expressed by placental isolates of Plasmodium falciparum. , 2002, Molecular and biochemical parasitology.

[25]  B. Gamain,et al.  The surface variant antigens of Plasmodium falciparum contain cross-reactive epitopes , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Ogobara K. Doumbo,et al.  The pathogenic basis of malaria , 2002, Nature.

[27]  T. Theander,et al.  Plasma Antibodies from Malaria-Exposed Pregnant Women Recognize Variant Surface Antigens on Plasmodium falciparum-Infected Erythrocytes in a Parity-Dependent Manner and Block Parasite Adhesion to Chondroitin Sulfate A1 , 2000, The Journal of Immunology.

[28]  J. Barnwell,et al.  Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum-infected erythrocytes to monocytes, endothelial, and C32 melanoma cells. , 1985, Journal of immunology.

[29]  S. Kyes,et al.  Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy. , 2002, The Journal of infectious diseases.

[30]  Thomas E. Wellems,et al.  Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum , 2000, Nature.

[31]  B. Gamain,et al.  Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Ockenhouse,et al.  Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Patrick E. Duffy,et al.  Adherence of Plasmodium falciparum to Chondroitin Sulfate A in the Human Placenta , 1996, Science.

[34]  A. Cowman,et al.  The chromosomal organization of the Plasmodium falciparum var gene family is conserved. , 1997, Molecular and biochemical parasitology.

[35]  R. Gwilliam,et al.  Sequence of Plasmodium falciparum chromosomes 1, 3–9 and 13 , 2002, Nature.

[36]  Kevin Marsh,et al.  The role of antibodies to Plasmodium falciparum-infected-erythrocyte surface antigens in naturally acquired immunity to malaria. , 2002, Trends in microbiology.

[37]  E. Whitehorn,et al.  A Generic Method for Expression and Use of “Tagged” Soluble Versions of Cell Surface Receptors , 1995, Bio/Technology.

[38]  B. Gamain,et al.  Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Mats Wahlgren,et al.  Developmental selection of var gene expression in Plasmodium falciparum , 1998, Nature.

[40]  S. Kyes,et al.  Var gene diversity in Plasmodium falciparum is generated by frequent recombination events. , 2000, Molecular and biochemical parasitology.

[41]  James Scott,et al.  Population genetics: Malaria susceptibility and CD36 mutation , 2000, Nature.

[42]  K. Kirchgatter,et al.  Association of Severe Noncerebral Plasmodium falciparum Malaria in Brazil With Expressed PfEMP1 DBL1α Sequences Lacking Cysteine Residues , 2002, Molecular Medicine.

[43]  X. Su,et al.  The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes , 1995, Cell.

[44]  B. Gamain,et al.  Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Y. Sterkers,et al.  Sequestration of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A, a receptor for maternal malaria: monoclonal antibodies against the native parasite ligand reveal pan-reactive epitopes in placental isolates. , 2002, Blood.

[46]  S. Kyes,et al.  Antigenic variation at the infected red cell surface in malaria. , 2001, Annual review of microbiology.

[47]  R. Hayward,et al.  Virulence and transmission success of the malarial parasite Plasmodium falciparum. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  I. Sherman,et al.  Plasmodium falciparum: pfalhesin and CD36 form an adhesin/receptor pair that is responsible for the pH-dependent portion of cytoadherence/sequestration. , 1994, Experimental parasitology.

[49]  Mats Wahlgren,et al.  The Semiconserved Head Structure of Plasmodium falciparum Erythrocyte Membrane Protein 1 Mediates Binding to Multiple Independent Host Receptors , 2000, The Journal of experimental medicine.

[50]  C. Ockenhouse,et al.  Activation of monocytes and platelets by monoclonal antibodies or malaria-infected erythrocytes binding to the CD36 surface receptor in vitro. , 1989, The Journal of clinical investigation.

[51]  Jonathan E. Allen,et al.  Sequence of Plasmodium falciparum chromosomes 2, 10, 11 and 14 , 2002, Nature.

[52]  A. Scherf,et al.  A distinct 5′ flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria , 2002, Molecular microbiology.

[53]  P. Kremsner,et al.  Variants of Plasmodium falciparum erythrocyte membrane protein 1 expressed by different placental parasites are closely related and adhere to chondroitin sulfate A. , 2001, The Journal of infectious diseases.

[54]  M. Smalley,et al.  The distribution of Plasmodium falciparum in the peripheral blood and bone marrow of Gambian children. , 1981, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[55]  M. Valiyaveettil,et al.  Characterization of Proteoglycans of Human Placenta and Identification of Unique Chondroitin Sulfate Proteoglycans of the Intervillous Spaces That Mediate the Adherence ofPlasmodium falciparum-infected Erythrocytes to the Placenta* , 2000, The Journal of Biological Chemistry.

[56]  A. Craig,et al.  Receptor-specific adhesion and clinical disease in Plasmodium falciparum. , 1997, The American journal of tropical medicine and hygiene.

[57]  B. Gamain,et al.  Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36. , 2001, Blood.

[58]  K. Kain,et al.  Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. , 2000, Blood.

[59]  R. Gwilliam,et al.  The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum , 1999, Nature.

[60]  M. Valiyaveettil,et al.  Structural Requirements for the Adherence ofPlasmodium falciparum-infected Erythrocytes to Chondroitin Sulfate Proteoglycans of Human Placenta* , 2000, The Journal of Biological Chemistry.