Binding brain better—matching
            <i>var</i>
            genes and endothelial receptors

Fleckenstein, Hannah; Portugal, Sílvia

doi:10.15252/emmm.201810137

Cited by 2 publications

(3 citation statements)

References 12 publications

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“…Despite extensive research, few formal associations between the expression of specific domains of PfEMP1 and the adhesion properties of clinical isolates of P. falciparum have been demonstrated ( 18 , 19 , 27 ). In order to fill this gap, we conducted a comparative study on CM and uncomplicated malaria (UM) in Beninese children, in which we attempted to correlate the cytoadherence phenotype of P. falciparum isolates with clinical presentation and the expression of specific domains of PfEMP1.…”

Section: Introductionmentioning

confidence: 99%

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

Joste

Guillochon

Fraering

et al. 2020

mBio

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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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Section: Introductionmentioning

confidence: 99%

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

Joste

Guillochon

Fraering

et al. 2020

mBio

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“…This cell enrichment procedure allows obtaining highly viable and pure parasite culture at late stages of trophozoite/schizonts. The trophozoite stage is when PfEMP1 is expressed on the surface of P. falciparum -infected red blood cells (iRBCs) and is the stage used for cytoadherence assays to microvascular endothelial cells [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…The adhesion receptors on the cell surface that are involved in sequestration mechanisms of the malaria parasite are associated with microvascular obstruction and clinical complications. In addition, other host receptors, such as EPCR, ICAM-1, and CD36, are involved in the sequestration of iRBCs to endothelial cells [ 8 , 9 , 10 , 11 , 12 ], as well as the P. falciparum erythrocyte membrane protein 1 (PfEMP1) [ 8 , 13 , 14 , 15 , 16 , 17 ] proteins of the parasites in the trophozoite and schizont stages [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Cerebral Malaria Model Applying Human Brain Organoids

Silva-Pedrosa

Campos

Fernandes

et al. 2023

Cells

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Neural injuries in cerebral malaria patients are a significant cause of morbidity and mortality. Nevertheless, a comprehensive research approach to study this issue is lacking, so herein we propose an in vitro system to study human cerebral malaria using cellular approaches. Our first goal was to establish a cellular system to identify the molecular alterations in human brain vasculature cells that resemble the blood–brain barrier (BBB) in cerebral malaria (CM). Through transcriptomic analysis, we characterized specific gene expression profiles in human brain microvascular endothelial cells (HBMEC) activated by the Plasmodium falciparum parasites. We also suggest potential new genes related to parasitic activation. Then, we studied its impact at brain level after Plasmodium falciparum endothelial activation to gain a deeper understanding of the physiological mechanisms underlying CM. For that, the impact of HBMEC-P. falciparum-activated secretomes was evaluated in human brain organoids. Our results support the reliability of in vitro cellular models developed to mimic CM in several aspects. These systems can be of extreme importance to investigate the factors (parasitological and host) influencing CM, contributing to a molecular understanding of pathogenesis, brain injury, and dysfunction.

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Binding brain better—matching var genes and endothelial receptors

Cited by 2 publications

References 12 publications

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

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

Cerebral Malaria Model Applying Human Brain Organoids

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