Targeting Malaria Virulence and Remodeling Proteins to the Host Erythrocyte

To establish infection in the host, malaria parasites export remodeling and virulence proteins into the erythrocyte. These proteins can traverse a series of membranes, including the parasite membrane, the parasitophorous vacuole membrane, and the erythrocyte membrane. We show that a conserved pentameric sequence plays a central role in protein export into the host cell and predict the exported proteome in Plasmodium falciparum. We identified 400 putative erythrocyte-targeted proteins corresponding to ∼8% of all predicted genes, with 225 virulence proteins and a further 160 proteins likely to be involved in remodeling of the host erythrocyte. The conservation of this signal across Plasmodium species has implications for the development of new antimalarials.

[1]  F. Cohen,et al.  Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray , 2003, Genome Biology.

[2]  David L. Tabb,et al.  A proteomic view of the Plasmodium falciparum life cycle , 2002, Nature.

[3]  V. de Lorenzo,et al.  The black cat/white cat principle of signal integration in bacterial promoters , 2001 .

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

[5]  M. Foley,et al.  Protein trafficking in malaria-infected erythrocytes. , 1998, International journal for parasitology.

[6]  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.

[7]  K. Haldar,et al.  Protein and lipid trafficking induced in erythrocytes infected by malaria parasites , 2002, Cellular microbiology.

[8]  Patricia De la Vega,et al.  Discovery of Gene Function by Expression Profiling of the Malaria Parasite Life Cycle , 2003, Science.

[9]  Travis Harrison,et al.  Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum-infected erythrocytes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Neil Hall,et al.  Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry , 2002, Nature.

[11]  Theodore F. Taraschi,et al.  Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes , 1995, Cell.

[12]  H. Shio,et al.  Primary structure and subcellular localization of the knob-associated histidine-rich protein of Plasmodium falciparum. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Mattei,et al.  Pfsbp1, a Maurer's cleft Plasmodium falciparum protein, is associated with the erythrocyte skeleton. , 2000, Molecular and biochemical parasitology.

[14]  R. Schroeder,et al.  Modulation of RNA function by aminoglycoside antibiotics , 2000, The EMBO journal.

[15]  Joseph D. Smith,et al.  Switches in expression of plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes , 1995, Cell.

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

[17]  R. Carter,et al.  Gene inactivation of Pf11‐1 of Plasmodium falciparum by chromosome breakage and healing: identification of a gametocyte‐specific protein with a potential role in gametogenesis. , 1992, The EMBO journal.

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

[19]  Jonathan E. Allen,et al.  Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii , 2002, Nature.