scholarly journals Plasmodium falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Xavier Sisquella ◽  
Thomas Nebl ◽  
Jennifer K Thompson ◽  
Lachlan Whitehead ◽  
Brian M Malpede ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Viscoelastic Properties ◽  
Kinase Inhibitors ◽  
Cytoskeletal Proteins ◽  
Initial Contact ◽  
Deformability Of Erythrocytes ◽  
Complex Process ◽  
Host Membrane ◽  
Erythrocyte Binding ◽  
Phosphorylation Cascade

The most lethal form of malaria in humans is caused by Plasmodium falciparum. These parasites invade erythrocytes, a complex process involving multiple ligand-receptor interactions. The parasite makes initial contact with the erythrocyte followed by dramatic deformations linked to the function of the Erythrocyte binding antigen family and P. falciparum reticulocyte binding-like families. We show EBA-175 mediates substantial changes in the deformability of erythrocytes by binding to glycophorin A and activating a phosphorylation cascade that includes erythrocyte cytoskeletal proteins resulting in changes in the viscoelastic properties of the host cell. TRPM7 kinase inhibitors FTY720 and waixenicin A block the changes in the deformability of erythrocytes and inhibit merozoite invasion by directly inhibiting the phosphorylation cascade. Therefore, binding of P. falciparum parasites to the erythrocyte directly activate a signaling pathway through a phosphorylation cascade and this alters the viscoelastic properties of the host membrane conditioning it for successful invasion.

scholarly journals Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

2013 ◽  
Vol 82 (1) ◽  
pp. 152-164 ◽  
Author(s):  
K. Sony Reddy ◽  
Alok K. Pandey ◽  
Hina Singh ◽  
Tajali Sahar ◽  
Amlabu Emmanuel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Expression System ◽  
Full Length ◽  
Blood Stage ◽  
Parasite Protein ◽  
Content Type ◽  
Erythrocyte Binding ◽  
Blood Stage Malaria

ABSTRACTPlasmodium falciparumreticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number ofP. falciparumstrains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 inEscherichia colithat exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number ofP. falciparumstrains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.P. falciparumhas the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwideP. falciparumstrains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

scholarly journals Erythrocyte Binding Protein PfRH5 Polymorphisms Determine Species-Specific Pathways of Plasmodium falciparum Invasion

2008 ◽  
Vol 4 (1) ◽  
pp. 40-51 ◽  
Author(s):  
Karen Hayton ◽  
Deepak Gaur ◽  
Anna Liu ◽  
Jonathan Takahashi ◽  
Bruce Henschen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Binding Protein ◽  
Erythrocyte Binding ◽  
Species Specific

scholarly journals Antibodies to Plasmodium falciparum Erythrocyte-binding Antigen-175 are Associated With Protection From Clinical Malaria

2011 ◽  
Vol 30 (12) ◽  
pp. 1037-1042 ◽  
Author(s):  
Matthew B. McCarra ◽  
George Ayodo ◽  
Peter O. Sumba ◽  
James W. Kazura ◽  
Ann M. Moormann ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Malaria ◽  
Erythrocyte Binding

Characterization of the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum

1990 ◽  
Vol 40 (2) ◽  
pp. 285-294 ◽  
Author(s):  
Palmer A. Orlandi ◽  
B. Kim Lee Sim ◽  
Jeffrey D. Chulay ◽  
J.David Haynes
Keyword(s):  
Plasmodium Falciparum ◽  
Erythrocyte Binding

scholarly journals Characterization of the Duffy-Binding-Like Domain of Plasmodium falciparum Blood-Stage Antigen 332

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Sandra Nilsson ◽  
Kirsten Moll ◽  
Davide Angeletti ◽  
Letusa Albrecht ◽  
Inari Kursula ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immunofluorescence Microscopy ◽  
Homology Model ◽  
Cross Reactivity ◽  
Blood Stage ◽  
Conserved Domain ◽  
Erythrocyte Binding ◽  
High Degree ◽  
Degree Of Similarity

Studies on Pf332, a major Plasmodium falciparum blood-stage antigen, have largely been hampered by the cross-reactive nature of antibodies generated against the molecule due to its high content of repeats, which are present in other malaria antigens. We previously reported the identification of a conserved domain in Pf332 with a high degree of similarity to the Duffy-binding-like (DBL) domains of the erythrocyte-binding-like (EBL) family. We here describe that antibodies towards Pf332-DBL are induced after repeated exposure to P. falciparum and that they are acquired early in life in areas of intense malaria transmission. Furthermore, a homology model of Pf332-DBL was found to be similar to the structure of the EBL-DBLs. Despite their similarities, antibodies towards Pf332-DBL did not display any cross-reactivity with EBL-proteins as demonstrated by immunofluorescence microscopy, Western blotting, and peptide microarray. Thus the DBL domain is an attractive region to use in further studies on the giant Pf332 molecule.

scholarly journals Role of a patatin-like phospholipase in Plasmodium falciparum gametogenesis and malaria transmission

2019 ◽  
Vol 116 (35) ◽  
pp. 17498-17508 ◽  
Author(s):  
Pallavi Singh ◽  
Aditi Alaganan ◽  
Kunal R. More ◽  
Audrey Lorthiois ◽  
Sabine Thiberge ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Membrane Remodeling ◽  
Gene Encoding ◽  
Conditional Deletion ◽  
Male Gametes ◽  
Complex Process ◽  
Intracellular Vesicles ◽  
Vesicle Secretion

Transmission of Plasmodium falciparum involves a complex process that starts with the ingestion of gametocytes by female Anopheles mosquitoes during a blood meal. Activation of gametocytes in the mosquito midgut triggers “rounding up” followed by egress of both male and female gametes. Egress requires secretion of a perforin-like protein, PfPLP2, from intracellular vesicles to the periphery, which leads to destabilization of peripheral membranes. Male gametes also develop flagella, which assist in binding female gametes for fertilization. This process of gametogenesis, which is key to malaria transmission, involves extensive membrane remodeling as well as vesicular discharge. Phospholipase A2 enzymes (PLA2) are known to mediate membrane remodeling and vesicle secretion in diverse organisms. Here, we show that a P. falciparum patatin-like phospholipase (PfPATPL1) with PLA2 activity plays a key role in gametogenesis. Conditional deletion of the gene encoding PfPATPL1 does not affect P. falciparum blood stage growth or gametocyte development but reduces efficiency of rounding up, egress, and exflagellation of gametocytes following activation. Interestingly, deletion of the PfPATPL1 gene inhibits secretion of PfPLP2, reducing the efficiency of gamete egress. Deletion of PfPATPL1 also reduces the efficiency of oocyst formation in mosquitoes. These studies demonstrate that PfPATPL1 plays a role in gametogenesis, thereby identifying PLA2 phospholipases such as PfPATPL1 as potential targets for the development of drugs to block malaria transmission.

scholarly journals Measurement of Antibody Levels against Region II of the Erythrocyte-Binding Antigen 175 of Plasmodium falciparum in an Area of Malaria Holoendemicity in Western Kenya

2004 ◽  
Vol 72 (2) ◽  
pp. 735-741 ◽  
Author(s):  
Eunita A. Ohas ◽  
John H. Adams ◽  
John N. Waitumbi ◽  
Alloys S. S. Orago ◽  
Arnoldo Barbosa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Sialic Acid ◽  
Inhibitory Activity ◽  
Western Kenya ◽  
Transmission Season ◽  
High Transmission ◽  
Exposed Population ◽  
Erythrocyte Binding ◽  
Antibody Levels ◽  
Region Ii

ABSTRACT Region II of the 175-kDa erythrocyte-binding antigen (EBA-175RII) of Plasmodium falciparum is functionally important in sialic acid-dependent erythrocyte invasion and is considered a prime target for an invasion-blocking vaccine. The objectives of this study were to (i) determine the prevalence of anti-EBA-175RII antibodies in a naturally exposed population, (ii) determine whether naturally acquired antibodies have a functional role by inhibiting binding of EBA-175RII to erythrocytes, and (iii) determine whether antibodies against EBA-175RII correlate with immunity to clinical malaria. We treated 301 lifelong residents of an area of malaria holoendemicity in western Kenya for malaria, monitored them during a high-transmission season, and identified 33 individuals who were asymptomatic despite parasitemia (clinically immune). We also identified 50 clinically susceptible individuals to serve as controls. These 83 individuals were treated and monitored again during the subsequent low-transmission season. Anti-EBA-175RII antibodies were present in 98.7% of the individuals studied. The antibody levels were relatively stable between the beginning and end of the high-transmission season and correlated with the plasma EBA-175RII erythrocyte-binding-inhibitory activity. There was no difference in anti-EBA-175RII levels or plasma EBA-175RII erythrocyte-binding-inhibitory activity between clinically immune and clinically susceptible groups. However, these parameters were higher in nonparasitemic than in parasitemic individuals at enrollment. These results suggest that although antibodies against EBA-175RII may be effective in suppressing some of the wild parasite strains, EBA-175RII is unlikely to be effective as a monovalent vaccine against malaria, perhaps due to allelic heterogeneity and/or presence of sialic acid-independent strains.

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