Abstract
The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells. Members of several variant surface protein families are expressed on infected blood cell surfaces. Of these, the largest and most ubiquitous are the Plasmodium-interspersed repeat (PIR) proteins, with more than 1,000 variants in some genomes. Their functions are mysterious, but differential pir gene expression associates with acute or chronic infection in a mouse malaria model. The membership of the PIR superfamily, and whether the family includes Plasmodium falciparum variant surface proteins, such as RIFINs and STEVORs, is controversial. Here we reveal the structure of the extracellular domain of a PIR from Plasmodium chabaudi We use structure-guided sequence analysis and molecular modeling to show that this fold is found across PIR proteins from mouse- and human-infective malaria parasites. Moreover, we show that RIFINs and STEVORs are not PIRs. This study provides a structure-guided definition of the PIRs and a molecular framework to understand their evolution.
Highlights
The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells
These studies suggest that the small variant surface antigens (VSAs) are molecules of infected blood cell surfaces and indicate that family expansion and diversification have occurred to allow them to undergo antigenic variation
A more virulent P. chabaudi strain, PcCB, expresses more of the pir genes associated with chronic infection than a less virulent strain, PcAS [30]
Summary
The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells. The largest and most ubiquitous are the Plasmodiuminterspersed repeat (PIR) proteins, with more than 1,000 variants in some genomes Their functions are mysterious, but differential pir gene expression associates with acute or chronic infection in a mouse malaria model. Natural infection with P. vivax induces antibodies that target VIRs [18], while unusual RIFIN-targeting antibodies found in adults in malaria endemic regions of Africa recognize infected erythrocytes [19,20,21] These studies suggest that the small VSAs are molecules of infected blood cell surfaces and indicate that family expansion and diversification have occurred to allow them to undergo antigenic variation.
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