Exported Proteins Required for Virulence and Rigidity of Plasmodium falciparum-Infected Human Erythrocytes

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Summary

A major part of virulence for Plasmodium falciparum malaria infection, the most lethal parasitic disease of humans, results from increased rigidity and adhesiveness of infected host red cells. These changes are caused by parasite proteins exported to the erythrocyte using novel trafficking machinery assembled in the host cell. To understand these unique modifications, we used a large-scale gene knockout strategy combined with functional screens to identify proteins exported into parasite-infected erythrocytes and involved in remodeling these cells. Eight genes were identified encoding proteins required for export of the parasite adhesin PfEMP1 and assembly of knobs that function as physical platforms to anchor the adhesin. Additionally, we show that multiple proteins play a role in generating increased rigidity of infected erythrocytes. Collectively these proteins function as a pathogen secretion system, similar to bacteria and may provide targets for antivirulence based therapies to a disease responsible for millions of deaths annually.

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Most cited references 33

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A translocation signal for delivery of oomycete effector proteins into host plant cells.

Stephen C Whisson, Petra Boevink, Lucy N. Moleleki … (2007)

Bacterial, oomycete and fungal plant pathogens establish disease by translocation of effector proteins into host cells, where they may directly manipulate host innate immunity. In bacteria, translocation is through the type III secretion system, but analogous processes for effector delivery are uncharacterized in fungi and oomycetes. Here we report functional analyses of two motifs, RXLR and EER, present in translocated oomycete effectors. We use the Phytophthora infestans RXLR-EER-containing protein Avr3a as a reporter for translocation because it triggers RXLR-EER-independent hypersensitive cell death following recognition within plant cells that contain the R3a resistance protein. We show that Avr3a, with or without RXLR-EER motifs, is secreted from P. infestans biotrophic structures called haustoria, demonstrating that these motifs are not required for targeting to haustoria or for secretion. However, following replacement of Avr3a RXLR-EER motifs with alanine residues, singly or in combination, or with residues KMIK-DDK--representing a change that conserves physicochemical properties of the protein--P. infestans fails to deliver Avr3a or an Avr3a-GUS fusion protein into plant cells, demonstrating that these motifs are required for translocation. We show that RXLR-EER-encoding genes are transcriptionally upregulated during infection. Bioinformatic analysis identifies 425 potential genes encoding secreted RXLR-EER class proteins in the P. infestans genome. Identification of this class of proteins provides unparalleled opportunities to determine how oomycetes manipulate hosts to establish infection.

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Plasmodium falciparum-infected human erythrocytes evade host immunity by expression of a cell-surface variant antigen and receptors for adherence to endothelial cells. These properties have been ascribed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), an antigenically diverse malarial protein of 200-350 kDa on the surface of parasitized erythrocytes (PEs). We describe the cloning of two related PfEMP1 genes from the Malayan Camp (MC) parasite strain. Antibodies generated against recombinant protein fragments of the genes were specific for MC strain PfEMP1 protein. These antibodies reacted only with the surface of MC strain PEs and blocked adherence of these cells to CD36 but without effect on adherence to thrombospondin. Multiple forms of the PfEMP1 gene are apparent in MC parasites. The molecular basis for antigenic variation in malaria and adherence of infected erythrocytes to host cells can now be pursued.

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The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes.

X Z Su, V M Heatwole, S P Wertheimer … (1995)

The human malaria parasite Plasmodium falciparum evades host immunity by varying the antigenic and adhesive character of infected erythrocytes. We describe a large and extremely diverse family of P. falciparum genes (var) that encode 200-350 kDa proteins having the expected properties of antigenically variant adhesion molecules. Predicted amino acid sequences of var genes show a variable extracellular segment with domains having receptor-binding features, a transmembrane sequence, and a terminal segment that is a probable submembrane anchor. There are 50-150 var genes on multiple parasite chromosomes, and some are in clustered arrangements. var probes detect two classes of transcripts in steady-state RNA: 7-9 kb var transcripts, and an unusual family of 1.8-2.4 kb transcripts that may be involved in expression or rearrangements of var genes.

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Author and article information

Journal

Journal ID (nlm-ta): Cell

Title: Cell

Publisher: Cell Press

ISSN (Print): 0092-8674

ISSN (Electronic): 1097-4172

Publication date PMC-release: 11 July 2008

Publication date (Print): 11 July 2008

Volume: 134

Issue: 1

Pages: 48-61

Affiliations

[1 ]The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia

[2 ]Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK

[3 ]Monash University, Department of Microbiology, Clayton 3800, Australia

[4 ]University of Oxford, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK

Author notes

[∗ ]Corresponding author cowman@ 123456wehi.edu.au

Article

Publisher ID: CELL3962

DOI: 10.1016/j.cell.2008.04.051

PMC ID: 2568870

PubMed ID: 18614010

SO-VID: be4e2564-6490-40be-9ee8-d36b4492e7a4

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This document may be redistributed and reused, subject to certain conditions.

History

Date received : 25 January 2008

Date revision received : 21 March 2008

Date accepted : 30 April 2008

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