Programmed Transcription of the var Gene Family, but Not of stevor , in Plasmodium falciparum Gametocytes

Abstract

The var genes encode Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins, a set of highly diverse surface-expressed proteins that mediate adhesion of erythrocytes infected with asexual bloodstage parasites to host endothelium. Switching among expressed PfEMP1 variants in the course of a bloodstage infection is a key component of antigenic variation, and thus immune evasion, by the parasite. The majority of var loci are found in the subtelomeric regions of P. falciparum chromosomes associated with members of other multigene families, including stevor. Both PfEMP1 and STEVOR are expressed in gametocytes, the transmissible parasite stage, but the role of these proteins in the biology of sexual-stage parasites remains unknown. PfEMP1 may continue to mediate antigenic variation in gametocytes, which need to persist in the host for many days before reaching maturity. Using quantitative reverse transcription-PCR and Northern hybridization, we demonstrate that transcription of a defined subset of type C var loci occurs during gametocyte development in vitro. This transcriptional program occurs in gametocytes regardless of the var expression phenotype of their asexual progenitors and therefore is subject to regulatory processes distinct from those that manage antigenic variation in the asexual parasite. In contrast, the same stevor variants are transcribed in both gametocytes and their asexual progenitors. We also provide evidence that for both asexual parasites and gametocytes, var and stevor transcription patterns are not linked to each other.

Limited Cross-Reactivity among Domains of the Plasmodium falciparum Clone 3D7 Erythrocyte Membrane Protein 1 Family

“…These var genes are present in many P. falciparum genomes, and within each subfamily stretches of high amino acid sequence similarity are found. Such PfEMP1 subfamilies are likely to induce cross-reactive antibodies, and it is conceivable that the global PfEMP1 repertoire is structured into distinct serologically cross-reactive types which could share functions such as binding identical receptors (e.g., CSA, CD36, and others) or being expressed at the same stage of the parasite life cycle (32). Thus, we would speculate cross-reactivity to be more frequent at the intergenomic level compared to the intragenomic level.…”

Plasmodium falciparumSTEVOR Proteins Are Highly Expressed in Patient Isolates and Located in the Surface Membranes of Infected Red Blood Cells and the Apical Tips of Merozoites

“…The array features were unflagged, and the array data that have median intensities greater than the local background plus one times the standard deviation of the background were extracted from the database. Quantitative real-time PCR was performed using 3D7 RNA from the different developmental stages and the published primers as previously described (32). The gene for the housekeeping protein actin was used to normalize the data (14).…”

“…The genes of var, rif, and stevor multigene families encoded on the parasite genome are thought to undergo switching and clonal variation, resulting in antigenic variation and thus prolonging the chronic infectivity of the parasite (7,15,17,19,21,23,24,31,32). The protein products of both the rif and var families have been shown to be transported to the surface of the infected red blood cell (iRBC) (10,17,19,23), and there is evidence that STEVOR proteins may also be located there (21).…”

“…Transcription of var genes is regulated epigenetically, ensuring that only a single functional gene is transcribed in each cell (9,28). In contrast, little is known about the transcriptional regulation of either rif or stevor, but it is apparent that stevor transcription is not coregulated with var despite similar locations of the genes (20,32).…”

Antigenic Variation in Plasmodium falciparum : Gene Organization and Regulation of the var Multigene Family

“…While the function of PfEMP1 proteins is best understood during the asexual cycle in erythrocytes, var gene expression is not limited to this stage of parasite development. PfEMP1 proteins are also expressed by early stage gametocyte-infected erythrocytes (41,91), the transmissible form of the parasite that is infective to mosquitoes. PfEMP1 tryptic fragments were also identified in mosquito salivary gland sporozoites (30).…”