scholarly journals An Erythrocyte Cytoskeleton-Binding Motif in Exported Plasmodium falciparum Proteins

2011 ◽  
Vol 10 (11) ◽  
pp. 1439-1447 ◽  
Author(s):  
Geoffrey K. Kilili ◽  
Douglas J. LaCount
Keyword(s):  
Plasmodium Falciparum ◽  
Host Cell ◽  
Aspartic Acid ◽  
Binding Motif ◽  
Host Cell Membrane ◽  
Content Type ◽  
C Terminus ◽  
Erythrocyte Surface ◽  
Protein 4.1R ◽  
Erythrocyte Cytoskeleton

ABSTRACTBinding of exported malaria parasite proteins to the host cell membrane and cytoskeleton contributes to the morphological, functional, and antigenic changes seen inPlasmodium falciparum-infected erythrocytes. One such exported protein that targets the erythrocyte cytoskeleton is the mature parasite-infected erythrocyte surface antigen (MESA), which interacts with the N-terminal 30-kDa domain of protein 4.1R via a 19-residue sequence. We report here that the MESA erythrocyte cytoskeleton-binding (MEC) domain is present in at least 13 otherP. falciparumproteins predicted to be exported to the host cell. An alignment of the putative cytoskeleton-binding sequences revealed a conserved aspartic acid at the C terminus that was omitted from the originally reported binding domain. Mutagenesis experiments demonstrated that this aspartic acid was required for the optimal binding of MESA to inside-out vesicles (IOVs) prepared from erythrocytes. Using pulldown assays, we characterized the binding of fragments encoding the MEC domains from PFE0040c/MESA and six other proteins (PF10_0378, PFA0675w, PFB0925w, PFD0095c, PFF1510w, and PFI1790w) to IOVs. All seven proteins bound to IOVs, with MESA showing the strongest affinity in saturation binding experiments. We further examined the interaction of the MEC domain proteins with components of the erythrocyte cytoskeleton and showed that MESA, PF10_0378, and PFA0675w coprecipitated full-length 4.1R from lysates prepared from IOVs. These data demonstrated that the MEC motif is present and functional in at least six otherP. falciparumproteins that are exported to the host cell cytoplasm.

scholarly journals Membrane and luminal proteins reach the apicoplast by different trafficking pathways in the malaria parasite Plasmodium falciparum

2017 ◽  
Author(s):  
Rahul Chaudhari ◽  
Vishakha Dey ◽  
Aishwarya Narayan ◽  
Shobhona Sharma ◽  
Swati Patankar
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Membrane ◽  
Membrane Protein ◽  
Host Cell ◽  
G Protein ◽  
Secretory Pathway ◽  
Protein Targeting ◽  
Acyl Carrier Protein ◽  
Secretory Proteins ◽  
Host Cell Membrane

The secretory pathway in Plasmodium falciparum has evolved to transport proteins to the host cell membrane and to an endosymbiotic organelle, the apicoplast. The latter can occur via the ER or the ER-Golgi route. Here, we study these three routes using proteins Erythrocyte Membrane Protein-1 (PfEMP1), Acyl Carrier Protein (ACP) and glutathione peroxidase-like thioredoxin peroxidase (PfTPxGl) and inhibitors of vesicular transport. As expected, the G protein dependent vesicular fusion inhibitor AlF4- and microtubule destabilizing drug vinblastine block the trafficking of PfEMP-1, a protein secreted to the host cell membrane. However, while both PfTPxGl and ACP are targeted to the apicoplast, only ACP trafficking remains unaffected by these treatments. This implies that G-protein dependent vesicles do not play a role in classical apicoplast protein targeting. Unlike the soluble protein ACP, we show that PfTPxGl is localized to the outermost membrane of the apicoplast. Thus, the parasite apicoplast acquires proteins via two different pathways: first, the vesicular trafficking pathway appears to handle not only secretory proteins, but an apicoplast membrane protein, PfTPxGl. Second, trafficking of apicoplast luminal proteins appear to be independent of G-protein coupled vesicles.

scholarly journals Membrane and luminal proteins reach the apicoplast by different trafficking pathways in the malaria parasite Plasmodium falciparum

2017 ◽  
Author(s):  
Rahul Chaudhari ◽  
Vishakha Dey ◽  
Aishwarya Narayan ◽  
Shobhona Sharma ◽  
Swati Patankar
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Membrane ◽  
Membrane Protein ◽  
Host Cell ◽  
G Protein ◽  
Secretory Pathway ◽  
Protein Targeting ◽  
Acyl Carrier Protein ◽  
Secretory Proteins ◽  
Host Cell Membrane

The secretory pathway in Plasmodium falciparum has evolved to transport proteins to the host cell membrane and to an endosymbiotic organelle, the apicoplast. The latter can occur via the ER or the ER-Golgi route. Here, we study these three routes using proteins Erythrocyte Membrane Protein-1 (PfEMP1), Acyl Carrier Protein (ACP) and glutathione peroxidase-like thioredoxin peroxidase (PfTPxGl) and inhibitors of vesicular transport. As expected, the G protein dependent vesicular fusion inhibitor AlF4- and microtubule destabilizing drug vinblastine block the trafficking of PfEMP-1, a protein secreted to the host cell membrane. However, while both PfTPxGl and ACP are targeted to the apicoplast, only ACP trafficking remains unaffected by these treatments. This implies that G-protein dependent vesicles do not play a role in classical apicoplast protein targeting. Unlike the soluble protein ACP, we show that PfTPxGl is localized to the outermost membrane of the apicoplast. Thus, the parasite apicoplast acquires proteins via two different pathways: first, the vesicular trafficking pathway appears to handle not only secretory proteins, but an apicoplast membrane protein, PfTPxGl. Second, trafficking of apicoplast luminal proteins appear to be independent of G-protein coupled vesicles.

scholarly journals The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 1036-1042 ◽  
Author(s):  
Xinhong Pei ◽  
Xinhua Guo ◽  
Ross Coppel ◽  
Souvik Bhattacharjee ◽  
Kasturi Haldar ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Antigen ◽  
Infected Erythrocyte ◽  
Host Cell Membrane ◽  
Acid Fragment ◽  
Erythrocyte Surface ◽  
Parasite Plasmodium Falciparum ◽  
Functional Consequences ◽  
Self Association ◽  
Resistance To Invasion

AbstractThe malaria parasite Plasmodium falciparum releases the ring-infected erythrocyte surface antigen (RESA) inside the red cell on entry. The protein migrates to the host cell membrane, where it binds to spectrin, but neither the nature of the interaction nor its functional consequences have previously been defined. Here, we identify the binding motifs involved in the interaction and describe a possible function. We have found that spectrin binds to a 108–amino acid fragment (residues 663-770) of RESA, and that this RESA fragment binds to repeat 16 of the β-chain, close to the labile dimer-dimer self-association site. We further show that the RESA fragment stabilizes the spectrin tetramer against dissociation into its constituent dimers, both in situ and in solution. This is accompanied by enhanced resistance of the cell to both mechanical and thermal degradation. Resealed erythrocytes containing RESA663-770 display resistance to invasion by merozoites of P falciparum. We infer that the evolutionary advantage of RESA to the parasite lies in its ability to prevent invasion of cells that are already host to a developing parasite, as well as possibly to guard the cell against thermal damage at the elevated body temperatures prevailing in febrile crises.

scholarly journals The Exported Chaperone PfHsp70x Is Dispensable for the Plasmodium falciparum Intraerythrocytic Life Cycle

mSphere ◽  
2017 ◽  
Vol 2 (5) ◽  
Author(s):  
David W. Cobb ◽  
Anat Florentin ◽  
Manuel A. Fierro ◽  
Michelle Krakowiak ◽  
Julie M. Moore ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Host Cell ◽  
Protein Trafficking ◽  
Human Disease ◽  
Clinical Manifestations ◽  
Parasite Protein ◽  
Content Type ◽  
Parasite Survival ◽  
Outstanding Question

ABSTRACT Half of the world’s population lives at risk for malaria. The intraerythrocytic life cycle of Plasmodium spp. is responsible for clinical manifestations of malaria; therefore, knowledge of the parasite’s ability to survive within the erythrocyte is needed to combat the deadliest agent of malaria, P. falciparum. An outstanding question in the field is how P. falciparum undertakes the essential process of trafficking its proteins within the host cell. In most organisms, chaperones such as Hsp70 are employed in protein trafficking. Of the Plasmodium species causing human disease, the chaperone PfHsp70x is unique to P. falciparum, and it is the only parasite protein of its kind exported to the host (S. Külzer et al., Cell Microbiol 14:1784–1795, 2012). This has placed PfHsp70x as an ideal target to inhibit protein trafficking and kill the parasite. However, we show that PfHsp70x is not required for export of parasite effectors and it is not essential for parasite survival inside the RBC. Export of parasite proteins into the host erythrocyte is essential for survival of Plasmodium falciparum during its asexual life cycle. While several studies described key factors within the parasite that are involved in protein export, the mechanisms employed to traffic exported proteins within the host cell are currently unknown. Members of the Hsp70 family of chaperones, together with their Hsp40 cochaperones, facilitate protein trafficking in other organisms, and are thus likely used by P. falciparum in the trafficking of its exported proteins. A large group of Hsp40 proteins is encoded by the parasite and exported to the host cell, but only one Hsp70, P. falciparum Hsp70x (PfHsp70x), is exported with them. PfHsp70x is absent in most Plasmodium species and is found only in P. falciparum and closely related species that infect apes. Herein, we have utilized clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing in P. falciparum to investigate the essentiality of PfHsp70x. We show that parasitic growth was unaffected by knockdown of PfHsp70x using both the dihydrofolate reductase (DHFR)-based destabilization domain and the glmS ribozyme system. Similarly, a complete gene knockout of PfHsp70x did not affect the ability of P. falciparum to proceed through its intraerythrocytic life cycle. The effect of PfHsp70x knockdown/knockout on the export of proteins to the host red blood cell (RBC), including the critical virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), was tested, and we found that this process was unaffected. These data show that although PfHsp70x is the sole exported Hsp70, it is not essential for the asexual development of P. falciparum. IMPORTANCE Half of the world’s population lives at risk for malaria. The intraerythrocytic life cycle of Plasmodium spp. is responsible for clinical manifestations of malaria; therefore, knowledge of the parasite’s ability to survive within the erythrocyte is needed to combat the deadliest agent of malaria, P. falciparum. An outstanding question in the field is how P. falciparum undertakes the essential process of trafficking its proteins within the host cell. In most organisms, chaperones such as Hsp70 are employed in protein trafficking. Of the Plasmodium species causing human disease, the chaperone PfHsp70x is unique to P. falciparum, and it is the only parasite protein of its kind exported to the host (S. Külzer et al., Cell Microbiol 14:1784–1795, 2012). This has placed PfHsp70x as an ideal target to inhibit protein trafficking and kill the parasite. However, we show that PfHsp70x is not required for export of parasite effectors and it is not essential for parasite survival inside the RBC.

scholarly journals Protein Kinase A Is Essential for Invasion of Plasmodium falciparum into Human Erythrocytes

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Mary-Louise Wilde ◽  
Tony Triglia ◽  
Danushka Marapana ◽  
Jennifer K. Thompson ◽  
Alexei A. Kouzmitchev ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Host Cell ◽  
Cell Invasion ◽  
Blood Cells ◽  
Host Cell Invasion ◽  
Parasite Invasion ◽  
Content Type ◽  
Kinase A

ABSTRACT Understanding the mechanisms behind host cell invasion by Plasmodium falciparum remains a major hurdle to developing antimalarial therapeutics that target the asexual cycle and the symptomatic stage of malaria. Host cell entry is enabled by a multitude of precisely timed and tightly regulated receptor-ligand interactions. Cyclic nucleotide signaling has been implicated in regulating parasite invasion, and an important downstream effector of the cAMP-signaling pathway is protein kinase A (PKA), a cAMP-dependent protein kinase. There is increasing evidence that P. falciparum PKA (PfPKA) is responsible for phosphorylation of the cytoplasmic domain of P. falciparum apical membrane antigen 1 (PfAMA1) at Ser610, a cAMP-dependent event that is crucial for successful parasite invasion. In the present study, CRISPR-Cas9 and conditional gene deletion (dimerizable cre) technologies were implemented to generate a P. falciparum parasite line in which expression of the catalytic subunit of PfPKA (PfPKAc) is under conditional control, demonstrating highly efficient dimerizable Cre recombinase (DiCre)-mediated gene excision and complete knockdown of protein expression. Parasites lacking PfPKAc show severely reduced growth after one intraerythrocytic growth cycle and are deficient in host cell invasion, as highlighted by live-imaging experiments. Furthermore, PfPKAc-deficient parasites are unable to phosphorylate PfAMA1 at Ser610. This work not only identifies an essential role for PfPKAc in the P. falciparum asexual life cycle but also confirms that PfPKAc is the kinase responsible for phosphorylating PfAMA1 Ser610. IMPORTANCE Malaria continues to present a major global health burden, particularly in low-resource countries. Plasmodium falciparum, the parasite responsible for the most severe form of malaria, causes disease through rapid and repeated rounds of invasion and replication within red blood cells. Invasion into red blood cells is essential for P. falciparum survival, and the molecular events mediating this process have gained much attention as potential therapeutic targets. With no effective vaccine available, and with the emergence of resistance to antimalarials, there is an urgent need for the development of new therapeutics. Our research has used genetic techniques to provide evidence of an essential protein kinase involved in P. falciparum invasion. Our work adds to the current understanding of parasite signaling processes required for invasion, highlighting PKA as a potential drug target to inhibit invasion for the treatment of malaria.

scholarly journals Live-Cell Imaging of Phosphoinositide Dynamics and Membrane Architecture during Legionella Infection

mBio ◽  
2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Stephen Weber ◽  
Maria Wagner ◽  
Hubert Hilbi
Keyword(s):  
Host Cell ◽  
Legionella Pneumophila ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Effector Proteins ◽  
Host Cells ◽  
Wild Type ◽  
Host Cell Membrane ◽  
Content Type ◽  
Temporal And Spatial

ABSTRACTThe causative agent of Legionnaires’ disease,Legionella pneumophila, replicates in amoebae and macrophages in a distinct membrane-bound compartment, theLegionella-containing vacuole (LCV). LCV formation is governed by the bacterial Icm/Dot type IV secretion system that translocates ~300 different “effector” proteins into host cells. Some of the translocated effectors anchor to the LCV membrane via phosphoinositide (PI) lipids. Here, we use the soil amoebaDictyostelium discoideum, producing fluorescent PI probes, to analyze the LCV PI dynamics by live-cell imaging. Upon uptake of wild-type or Icm/Dot-deficientL. pneumophila, PtdIns(3,4,5)P3transiently accumulated for an average of 40 s on early phagosomes, which acquired PtdIns(3)Pwithin 1 min after uptake. Whereas phagosomes containing ΔicmTmutant bacteria remained decorated with PtdIns(3)P, more than 80% of wild-type LCVs gradually lost this PI within 2 h. The process was accompanied by a major rearrangement of PtdIns(3)P-positive membranes condensing to the cell center. PtdIns(4)Ptransiently localized to early phagosomes harboring wild-type or ΔicmT L. pneumophilaand was cleared within minutes after uptake. During the following 2 h, PtdIns(4)Psteadily accumulated only on wild-type LCVs, which maintained a discrete PtdIns(4)Pidentity spatially separated from calnexin-positive endoplasmic reticulum (ER) for at least 8 h. The separation of PtdIns(4)P-positive and ER membranes was even more pronounced for LCVs harboring ΔsidC-sdcAmutant bacteria defective for ER recruitment, without affecting initial bacterial replication in the pathogen vacuole. These findings elucidate the temporal and spatial dynamics of PI lipids implicated in LCV formation and provide insight into host cell membrane and effector protein interactions.IMPORTANCEThe environmental bacteriumLegionella pneumophilais the causative agent of Legionnaires’ pneumonia. The bacteria form in free-living amoebae and mammalian immune cells a replication-permissive compartment, theLegionella-containing vacuole (LCV). To subvert host cell processes, the bacteria secrete the amazing number of ~300 different proteins into host cells. Some of these proteins bind phosphoinositide (PI) lipids to decorate the LCV. PI lipids are crucial factors involved in host cell membrane dynamics and LCV formation. UsingDictyosteliumamoebae producing one or two distinct fluorescent probes, we elucidated the dynamic LCV PI pattern in high temporal and spatial resolution. Notably, the endocytic PI lipid PtdIns(3)Pwas slowly cleared from LCVs, thus incapacitating the host cell’s digestive machinery, while PtdIns(4)Pgradually accumulated on the LCV, enabling critical interactions with host organelles. The LCV PI pattern underlies the spatiotemporal configuration of bacterial effector proteins and therefore represents a crucial aspect of LCV formation.

scholarly journals Origins of the parasitophorous vacuole membrane of the malaria parasite, Plasmodium falciparum, in human red blood cells

1992 ◽  
Vol 102 (3) ◽  
pp. 527-532 ◽  
Author(s):  
A.R. Dluzewski ◽  
G.H. Mitchell ◽  
P.R. Fryer ◽  
S. Griffiths ◽  
R.J. Wilson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Membrane ◽  
Host Cell ◽  
Malaria Parasite ◽  
Parasitophorous Vacuole ◽  
Parasitophorous Vacuole Membrane ◽  
Host Cell Membrane ◽  
Vacuole Membrane ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

We have attempted to determine whether the parasitophorous vacuole membrane, in which the malaria parasite (merozoite) encapsulates itself when it enters a red blood cell, is derived from the host cell plasma membrane, as the appearance of the invasion process in the electron microscope has been taken to suggest, or from lipid material stored in the merozoite. We have incorporated into the red cell membrane a haptenic phospholipid, phosphatidylethanolamine, containing an NBD (N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)) group, substituted in the acyl chain, and allowed it to translocate into the inner bilayer leaflet. After invasion of these labelled cells by the parasite, Plasmodium falciparum, immuno-gold electron microscopy was used to follow the distribution of the labelled lipid; this was found to be overwhelmingly in favour of the host cell membrane relative to the parasitophorous vacuole. Merozoites of P. knowlesi were allowed to attach irreversibly to red cells without invasion, using the method of pretreatment with cytochalasin. The region of contact between the merozoite and the host cell membrane was in all cases devoid of the labelled phosphatidylethanolamine. These results lead us to infer that the parasitophorous vacuole membrane is derived wholly or partly from lipid preexisting in the merozoite.

scholarly journals Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
J. Stephan Wichers ◽  
Judith A. M. Scholz ◽  
Jan Strauss ◽  
Susanne Witt ◽  
Andrés Lill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Host Cell ◽  
Cell Invasion ◽  
Surface Antigens ◽  
Membrane Topology ◽  
Host Cell Invasion ◽  
Content Type ◽  
Variant Surface Antigens

ABSTRACT During its intraerythrocytic development, the malaria parasite Plasmodium falciparum exposes variant surface antigens (VSAs) on infected erythrocytes to establish and maintain an infection. One family of small VSAs is the polymorphic STEVOR proteins, which are marked for export to the host cell surface through their PEXEL signal peptide. Interestingly, some STEVORs have also been reported to localize to the parasite plasma membrane and apical organelles, pointing toward a putative function in host cell egress or invasion. Using deep RNA sequencing analysis, we characterized P. falciparum stevor gene expression across the intraerythrocytic development cycle, including free merozoites, in detail and used the resulting stevor expression profiles for hierarchical clustering. We found that most stevor genes show biphasic expression oscillation, with maximum expression during trophozoite stages and a second peak in late schizonts. We selected four STEVOR variants, confirmed the expected export of these proteins to the host cell membrane, and tracked them to a secondary location, either to the parasite plasma membrane or the secretory organelles of merozoites in late schizont stages. We investigated the function of a particular STEVOR that showed rhoptry localization and demonstrated its role at the parasite-host interface during host cell invasion by specific antisera and targeted gene disruption. Experimentally determined membrane topology of this STEVOR revealed a single transmembrane domain exposing the semiconserved as well as variable protein regions to the cell surface. IMPORTANCE Malaria claims about half a million lives each year. Plasmodium falciparum, the causative agent of the most severe form of the disease, uses proteins that are translocated to the surface of infected erythrocytes for immune evasion. To circumvent the detection of these gene products by the immune system, the parasite evolved a complex strategy that includes gene duplications and elaborate sequence polymorphism. STEVORs are one family of these variant surface antigens and are encoded by about 40 genes. Using deep RNA sequencing of blood-stage parasites, including free merozoites, we first established stevor expression of the cultured isolate and compared it with published transcriptomes. We reveal a biphasic expression of most stevor genes and confirm this for individual STEVORs at the protein level. The membrane topology of a rhoptry-associated variant was experimentally elucidated and linked to host cell invasion, underlining the importance of this multifunctional protein family for parasite proliferation.

scholarly journals PfEMP1 A-Type ICAM-1-Binding Domains Are Not Associated with Cerebral Malaria in Beninese Children

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
V. Joste ◽  
E. Guillochon ◽  
J. Fraering ◽  
B. Vianou ◽  
L. Watier ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Cell Lines ◽  
Receptor Binding ◽  
Binding Motif ◽  
Endothelial Protein C Receptor ◽  
Content Type ◽  
Binding Domains ◽  
Cerebrovascular Endothelium

ABSTRACT PfEMP1 is the major antigen involved in Plasmodium falciparum-infected erythrocyte sequestration in cerebrovascular endothelium. While some PfEMP1 domains have been associated with clinical phenotypes of malaria, formal associations between the expression of a specific domain and the adhesion properties of clinical isolates are limited. In this context, 73 cerebral malaria (CM) and 98 uncomplicated malaria (UM) Beninese children were recruited. We attempted to correlate the cytoadherence phenotype of Plasmodium falciparum isolates with the clinical presentation and the expression of specific PfEMP1 domains. Cytoadherence level on Hbec-5i and CHO-ICAM-1 cell lines and var genes expression were measured. We also investigated the prevalence of the ICAM-1-binding amino acid motif and dual receptor-binding domains, described as a potential determinant of cerebral malaria pathophysiology. We finally evaluated IgG levels against PfEMP1 recombinant domains (CIDRα1.4, DBLβ3, and CIDRα1.4-DBLβ3). CM isolates displayed higher cytoadherence levels on both cell lines, and we found a correlation between CIDRα1.4-DBLβ1/3 domain expression and CHO-ICAM-1 cytoadherence level. Endothelial protein C receptor (EPCR)-binding domains were overexpressed in CM isolates compared to UM whereas no difference was found in ICAM-1-binding DBLβ1/3 domain expression. Surprisingly, both CM and UM isolates expressed ICAM-1-binding motif and dual receptor-binding domains. There was no difference in IgG response against DBLβ3 between CM and UM isolates expressing ICAM-1-binding DBLβ1/3 domain. It raises questions about the role of this motif in CM pathophysiology, and further studies are needed, especially on the role of DBLβ1/3 without the ICAM-1-binding motif. IMPORTANCE Cerebral malaria pathophysiology remains unknown despite extensive research. PfEMP1 proteins have been identified as the main Plasmodium antigen involved in cerebrovascular endothelium sequestration, but it is unclear which var gene domain is involved in Plasmodium cytoadhesion. EPCR binding is a major determinant of cerebral malaria whereas the ICAM-1-binding role is still questioned. Our study confirmed the EPCR-binding role in CM pathophysiology with a major overexpression of EPCR-binding domains in CM isolates. In contrast, ICAM-1-binding involvement appears less obvious with A-type ICAM-1-binding and dual receptor-binding domain expression in both CM and UM isolates. We did not find any variations in ICAM-1-binding motif sequences in CM compared to UM isolates. UM and CM patients infected with isolates expressing the ICAM-1-binding motif displayed similar IgG levels against DBLβ3 recombinant protein. Our study raises interrogations about the role of these domains in CM physiopathology and questions their use in vaccine strategies against cerebral malaria.

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