scholarly journals Delivery of the Malaria Virulence Protein PfEMP1 to the Erythrocyte Surface Requires Cholesterol-Rich Domains

2006 ◽  
Vol 5 (5) ◽  
pp. 849-860 ◽  
Author(s):  
Sarah Frankland ◽  
Akinola Adisa ◽  
Paul Horrocks ◽  
Theodore F. Taraschi ◽  
Timothy Schneider ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Infected Erythrocyte ◽  
Membrane Microdomains ◽  
Human Malaria Parasite ◽  
Vesicle Budding ◽  
Erythrocyte Invasion ◽  
Major Virulence Factor ◽  
Erythrocyte Surface ◽  
Virulence Protein ◽  
Maurer's Clefts

ABSTRACT The particular virulence of the human malaria parasite Plasmodium falciparum derives from export of parasite-encoded proteins to the surface of the mature erythrocytes in which it resides. The mechanisms and machinery for the export of proteins to the erythrocyte membrane are largely unknown. In other eukaryotic cells, cholesterol-rich membrane microdomains or “rafts” have been shown to play an important role in the export of proteins to the cell surface. Our data suggest that depletion of cholesterol from the erythrocyte membrane with methyl-β-cyclodextrin significantly inhibits the delivery of the major virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1). The trafficking defect appears to lie at the level of transfer of PfEMP1 from parasite-derived membranous structures within the infected erythrocyte cytoplasm, known as the Maurer's clefts, to the erythrocyte membrane. Thus our data suggest that delivery of this key cytoadherence-mediating protein to the host erythrocyte membrane involves insertion of PfEMP1 at cholesterol-rich microdomains. GTP-dependent vesicle budding and fusion events are also involved in many trafficking processes. To determine whether GTP-dependent events are involved in PfEMP1 trafficking, we have incorporated non-membrane-permeating GTP analogs inside resealed erythrocytes. Although these nonhydrolyzable GTP analogs reduced erythrocyte invasion efficiency and partially retarded growth of the intracellular parasite, they appeared to have little direct effect on PfEMP1 trafficking.

scholarly journals Trafficking and Association of Plasmodium falciparum MC-2TM with the Maurer’s Clefts

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 431
Author(s):  
Raghavendra Yadavalli ◽  
John W. Peterson ◽  
Judith A. Drazba ◽  
Tobili Y. Sam-Yellowe
Keyword(s):  
Plasmodium Falciparum ◽  
Erythrocyte Membrane ◽  
Sodium Carbonate ◽  
Infected Erythrocyte ◽  
Brefeldin A ◽  
Specific Expression ◽  
Lipid Interactions ◽  
And Topology ◽  
Streptolysin O ◽  
Maurer's Clefts

In this study, we investigated stage specific expression, trafficking, solubility and topology of endogenous PfMC-2TM in P. falciparum (3D7) infected erythrocytes. Following Brefeldin A (BFA) treatment of parasites, PfMC-2TM traffic was evaluated using immunofluorescence with antibodies reactive with PfMC-2TM. PfMC-2TM is sensitive to BFA treatment and permeabilization of infected erythrocytes with streptolysin O (SLO) and saponin, showed that the N and C-termini of PfMC-2TM are exposed to the erythrocyte cytoplasm with the central portion of the protein protected in the MC membranes. PfMC-2TM was expressed as early as 4 h post invasion (hpi), was tightly colocalized with REX-1 and trafficked to the erythrocyte membrane without a change in solubility. PfMC-2TM associated with the MC and infected erythrocyte membrane and was resistant to extraction with alkaline sodium carbonate, suggestive of protein-lipid interactions with membranes of the MC and erythrocyte. PfMC-2TM is an additional marker of the nascent MCs.

scholarly journals Role of the Plasmodium falciparum mature-parasite-infected erythrocyte surface antigen (MESA/PfEMP-2) in malarial infection of erythrocytes

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3196-3204 ◽  
Author(s):  
C Magowan ◽  
RL Coppel ◽  
AO Lau ◽  
MM Moronne ◽  
G Tchernia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Erythrocyte Membrane ◽  
Surface Antigen ◽  
Infected Erythrocyte ◽  
Spontaneous Mutant ◽  
Protein 4.1 ◽  
Erythrocyte Surface ◽  
Skeletal Protein ◽  
Parasite Viability

Abstract During intraerythrocytic growth of Plasmodium falciparum, several parasite proteins are transported from the parasite to the erythrocyte membrane, where they bind to membrane skeletal proteins. Mature-parasite-infected erythrocyte surface antigen (MESA) has previously been shown to associate with host erythrocyte membrane skeletal protein 4.1. Using a spontaneous mutant of P falciparum that has lost the ability to synthesize MESA and 4.1-deficient erythrocytes, we examined growth of MESA(+) and MESA(-) parasites in normal and 4.1-deficient erythrocytes. Viability of MESA(+) parasites was reduced in 4.1-deficient erythrocytes as compared with that for normal erythrocytes, but MESA(-) parasites grew equally well in 4.1-deficient and normal erythrocytes. Cytoadherence of MESA(+)- and MESA (-)-parasitized normal and 4.1-deficient erythrocytes to C32 melanoma cells was similar, indicating that neither protein 4.1 nor MESA plays a major role in cytoadherence of infected erythrocytes. Localization of MESA in normal and 4.1-deficient erythrocytes was examined by confocal microscopy. MESA was diffusely distributed in the cytosol of 4.1-deficient erythrocytes but was membrane-associated in normal erythrocytes. These findings suggest that MESA binding to protein 4.1 plays a major role in intraerythrocytic parasite viability.

Characterisation of Plasmodium falciparum RESA-like protein peptides that bind specifically to erythrocytes and inhibit invasion

2007 ◽  
Vol 388 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Luis Eduardo Rodriguez ◽  
Ricardo Vera ◽  
John Valbuena ◽  
Hernando Curtidor ◽  
Javier Garcia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Surface ◽  
Binding Assays ◽  
Gene Encoding ◽  
Trophozoite Stage ◽  
Rbc Membrane ◽  
Erythrocyte Invasion ◽  
Erythrocyte Surface ◽  
Maurer's Clefts

Abstract The Plasmodium falciparum ring-erythrocyte surface antigen (RESA)-like putative protein was identified and characterised. PCR and RT-PCR assays revealed that the gene encoding this protein was both present and being transcribed in P. falciparum strain FCB-2 16 h after erythrocyte invasion. Indirect immunofluorescence studies detected this protein in infected erythrocyte (IE) cytosol in dense fluorescent granules similar to Maurer's clefts at 16–20 h (parasites in ring and trophozoite stages) and very strongly on IE membranes at 22 h, suggesting that it is synthesised during early ring stages (16 h) and transported to the infected red blood cell (RBC) membrane surface during the trophozoite stage (22 h). Western blotting showed that antisera produced against polymerised synthetic peptides of this protein recognised a 72-kDa band in P. falciparum schizont lysate. P. falciparum RESA-like peptides used in normal RBC binding assays revealed that peptides 30326 (101NAEKI LGFDD KNILE ALDLFY120), 30334 (281RVTWK KLRTK MIKAL KKSLTY300) and 30342 (431SSPQR LKFTA GGGFC GKLRNY450) bind with high activity and saturability, presenting nM affinity constants. These peptides contain α-helical structural elements, as determined by circular dichroism, and inhibit P. falciparum in vitro invasion of normal RBCs by up to 91%, suggesting that some RESA-like protein regions are involved in intra-erythrocyte stage P. falciparum invasion.

scholarly journals Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion

PLoS Biology ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. e3001408
Author(s):  
Anja C. Schlott ◽  
Ellen Knuepfer ◽  
Judith L. Green ◽  
Philip Hobson ◽  
Aaron J. Borg ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Infected Erythrocyte ◽  
Complex Function ◽  
Pleiotropic Effect ◽  
Substantial Effect ◽  
Parasite Development ◽  
Human Malaria Parasite ◽  
Erythrocyte Invasion ◽  
Erythrocytic Cycle ◽  
Parasite Egress

We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of “pseudoschizonts,” which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition.

scholarly journals Virulence determinant, PTP7, controls vesicle budding from the Maurer’s clefts, adhesin protein trafficking and host cell remodeling in Plasmodium falciparum

2021 ◽  
Author(s):  
Olivia M. S. Carmo ◽  
Gerald J Shami ◽  
Dezerae Cox ◽  
Boyin Liu ◽  
Adam J Blanch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Surface ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Protein Trafficking ◽  
Low Complexity ◽  
Vesicle Budding ◽  
Cell Remodeling ◽  
Virulence Protein ◽  
Maurer's Clefts

Presentation of the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpins P. falciparum malaria pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurer’s cleft, and the red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurer’s clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface.  We show that an expanded low complexity sequence in the C-terminal region of PTP7, found only in the Laverania clade of Plasmodium , is critical for efficient virulence protein trafficking.

scholarly journals Antibody Levels to Plasmodium falciparum Erythrocyte Membrane Protein 1-DBLγ11 and DBLδ-1 Predict Reduction in Parasite Density

mSystems ◽  
2021 ◽  
Author(s):  
Brittany N. Araj ◽  
Bruce Swihart ◽  
Robert Morrison ◽  
Patricia Gonzales Hurtado ◽  
Andrew Teo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Protein ◽  
Erythrocyte Membrane ◽  
Infected Erythrocyte ◽  
Severe Disease ◽  
Content Type ◽  
Erythrocyte Membrane Protein ◽  
Erythrocyte Surface ◽  
Antibody Levels ◽  
Falciparum Erythrocyte Membrane Protein

Plasmodium infection causes devastating disease and high mortality in young children. Immunity develops progressively as children acquire protection against severe disease, although reinfections and recrudescences still occur throughout life in areas of endemicity, partly due to parasite immunoevasion via switching of variant proteins such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the infected erythrocyte surface.

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