Plasmodium falciparum variant STEVOR antigens are expressed in merozoites and possibly associated with erythrocyte invasion

Khattab, Ayman; Bonow, Insa; Schreiber, Nadine; Petter, Michaela; Schmetz, Christel; Klinkert, Mo‐Quen

doi:10.1186/1475-2875-7-137

Cited by 35 publications

(44 citation statements)

References 22 publications

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“…Interestingly, the ex vivo , non-binding parasites failed to express var , A-type rif and stevor genes whereas B-type rif and Pfmc-2TM , respectively, were found to be expressed, suggesting that the latter two gene families may encode proteins that are not targeted to the erythrocyte surface and therefore do not participate in endothelial receptor binding. Indeed, surface exposition of PfEMP-1 and recently of STEVOR has been already demonstrated [6], [21] and various studies imply that A-type RIFIN proteins are transported via the Maurer's clefts to the erythrocyte membrane [16], [19], [45]. Moreover, PfEMP-1, RIFIN and STEVOR proteins were previously determined as targets of the adaptive antibody-mediated immunity against P. falciparum malaria [6], [46], [47], suggesting exposure of these proteins at the outside of the erythrocyte membrane bilayer, where they are accessible to serum antibodies.…”

Section: Discussionmentioning

confidence: 98%

Absence of Erythrocyte Sequestration and Lack of Multicopy Gene Family Expression in Plasmodium falciparum from a Splenectomized Malaria Patient

et al. 2009

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BackgroundTo avoid spleen-dependent killing mechanisms parasite-infected erythrocytes (IE) of Plasmodium falciparum malaria patients have the capacity to bind to endothelial receptors. This binding also known as sequestration, is mediated by parasite proteins, which are targeted to the erythrocyte surface. Candidate proteins are those encoded by P. falciparum multicopy gene families, such as var, rif, stevor or PfMC-2TM. However, a direct in vivo proof of IE sequestration and expression of multicopy gene families is still lacking. Here, we report on the analysis of IE from a black African immigrant, who received the diagnosis of a malignant lymphoproliferative disorder and subsequently underwent splenectomy. Three weeks after surgery, the patient experienced clinical falciparum malaria with high parasitemia and circulating developmental parasite stages usually sequestered to the vascular endothelium such as late trophozoites, schizonts or immature gametocytes.Methodology/Principal FindingsInitially, when isolated from the patient, the infected erythrocytes were incapable to bind to various endothelial receptors in vitro. Moreover, the parasites failed to express the multicopy gene families var, A-type rif and stevor but expression of B-type rif and PfMC-2TM genes were detected. In the course of in vitro cultivation, the parasites started to express all investigated multicopy gene families and concomitantly developed the ability to adhere to endothelial receptors such as CD36 and ICAM-1, respectively.Conclusion/SignificanceThis case strongly supports the hypothesis that parasite surface proteins such as PfEMP1, A-type RIFIN or STEVOR are involved in interactions of infected erythrocytes with endothelial receptors mediating sequestration of mature asexual and immature sexual stages of P. falciparum. In contrast, multicopy gene families coding for B-type RIFIN and PfMC-2TM proteins may not be involved in sequestration, as these genes were transcribed in infected but not sequestered erythrocytes.

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Section: Discussionmentioning

confidence: 98%

Absence of Erythrocyte Sequestration and Lack of Multicopy Gene Family Expression in Plasmodium falciparum from a Splenectomized Malaria Patient

et al. 2009

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“…In the case of P. falciparum , the expression of RIFIN and STEVOR on the iRBC surface (Fernandez et al, 1999; Kyes et al, 1999; Niang et al, 2009) implies that they confer an important survival advantage. The expression of STEVOR in multiple parasite stages including merozoites (Blythe et al, 2008; Khattab et al, 2008; Khattab and Meri, 2011; Petter et al, 2007), sporozoites and gametocytes (McRobert et al, 2004) suggests that STEVOR mediates multiple distinct functions (Blythe et al, 2004). The observation that some synthetic peptides based on a STEVOR sequence had some RBC binding activity (Garcia et al, 2005), suggested that STEVOR could function in the invasion process by enhancing initial interaction of merozoites with RBC.…”

Section: Introductionmentioning

confidence: 99%

STEVOR Is a Plasmodium falciparum Erythrocyte Binding Protein that Mediates Merozoite Invasion and Rosetting

Niang

Bei

Madnani

et al. 2014

Cell Host & Microbe

158

196

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Summary Variant surface antigens play an important role in the pathogenesis of Plasmodium falciparum malaria. To date, intensive work has mainly focused on the role in parasite virulence of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) encoded by the var multigene family. Two other multigene families coding for STEVOR and RIFIN have recently also been shown to be expressed in the invasive merozoite as well as on the surface of the infected erythrocyte, implicating them as potential parasite virulence factors. Here we report that STEVOR is an erythrocyte-binding protein recognizing Glycophorin C on the red blood cell (RBC) surface. STEVOR expression on the RBC leads to PfEMP1-independent rosette formation, while antibodies targeting STEVOR in the merozoite can effectively inhibit invasion. Our results suggest a novel role of STEVOR in enabling infected erythrocytes at the schizont stage to bind uninfected erythrocytes to form rosettes, thereby protecting released merozoites from immune detection.

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“…[14][15][16] The encoded STEVOR proteins exhibit a semiconserved N-terminal domain and a central variable domain exposed on the erythrocyte surface, whereas the conserved C-terminal domain is cytoplasmic. 17,18 Besides their role in invasion, adhesion, and rosetting in asexual stages, [19][20][21][22] STEVOR proteins have been shown to impact the deformability of the infected erythrocyte in mature asexual parasites and immature sexual stages. 6,23 However, the mechanism underlying STEVOR-mediated changes in erythrocyte deformability remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

Naissant

Dupuy

Duffier

et al. 2016

Blood

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Key Points• P falciparum STEVORs interact with the erythrocyte cytoskeletal ankyrin complex.• Infected erythrocyte deformability is regulated by PKA-mediated phosphorylation of STEVOR cytoplasmic domain.Deformability of Plasmodium falciparum gametocyte-infected erythrocytes (GIEs) allows them to persist for several days in blood circulation and to ensure transmission to mosquitoes. Here, we investigate the mechanism by which the parasite proteins STEVOR (SubTElomeric Variable Open Reading frame) exert changes on GIE deformability. Using the microsphiltration method, immunoprecipitation, and mass spectrometry, we produce evidence that GIE stiffness is dependent on the cytoplasmic domain of STEVOR that interacts with ankyrin complex at the erythrocyte skeleton. Moreover, we show that GIE deformability is regulated by protein kinase A (PKA)-mediated phosphorylation of the STEVOR C-terminal domain at a specific serine residue (S 324 ). Finally, we show that the increase of GIE stiffness induced by sildenafil (Viagra) is dependent on STEVOR phosphorylation status and on another independent mechanism. These data provide new insights into mechanisms by which phosphodiesterase inhibitors may block malaria parasite transmission. (Blood. 2016;127(24):e42-e53)

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Plasmodium falciparum variant STEVOR antigens are expressed in merozoites and possibly associated with erythrocyte invasion

Cited by 35 publications

References 22 publications

Absence of Erythrocyte Sequestration and Lack of Multicopy Gene Family Expression in Plasmodium falciparum from a Splenectomized Malaria Patient

Absence of Erythrocyte Sequestration and Lack of Multicopy Gene Family Expression in Plasmodium falciparum from a Splenectomized Malaria Patient

STEVOR Is a Plasmodium falciparum Erythrocyte Binding Protein that Mediates Merozoite Invasion and Rosetting

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

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