Identification of Plasmodium falciparum and host factors associated with cerebral malaria: description of the protocol for a prospective, case-control study in Benin (NeuroCM)

Joste, Valentin; Maurice, Laurine; Bertin, Gwladys; Aubouy, Agnès; Boumédiène, Farid; Houzé, Sandrine; Ajzenberg, Daniel; Argy, Nicolas; Massougbodji, Achille; Dossou-Dagba, Ida; Alao, Maroufou Jules; Cot, Michel; Deloron, Philippe; Faucher, Jean‐François

doi:10.1136/bmjopen-2018-027378

Cited by 10 publications

(17 citation statements)

References 36 publications

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“…We carried out fundus examination for each cerebral malaria patient within 1 day of inclusion ( 35 ). Of note, 67% of cerebral malaria children had MR. No difference in var gene expression and cytoadherence level was evidenced between children with MR and NF ( Table S2 ), as previously described ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, we defined UM by fever at inclusion or within 24 h before and positive thick or thin blood smear, without clinical or biological sign of severe malaria. We defined CM by a Blantyre score at diagnosis of ≤2 and a confirmed presence of P. falciparum infection with exclusion of other causes for coma, particularly meningitis ( 35 ). Peripheral venous blood samples have been collected from all study individuals in a Vacutainer tube containing EDTA.…”

Section: Methodsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

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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“…Our present work is part of a larger project called NeuroCM [ 11 , 12 ], whose main goal is to identify the causative and remedial factors of neuroinflammation in the context of CM. From the data collected in this prospective study, we undertook a retrospective analysis of the determinants of death in small children admitted with non-traumatic coma in South Benin, focused on the etiologies, clinical history, clinical and biological characteristics at admission, and management of the children.…”

Section: Introductionmentioning

confidence: 99%

Non-traumatic coma in young children in Benin: are viral and bacterial infections gaining ground on cerebral malaria?

et al. 2022

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Background While malaria morbidity and mortality have declined since 2000, viral central nervous system infections appear to be an important, underestimated cause of coma in malaria-endemic Eastern Africa. We aimed to describe the etiology of non-traumatic comas in young children in Benin, as well as their management and early outcomes, and to identify factors associated with death. Methods From March to November 2018, we enrolled all HIV-negative children aged between 2 and 6 years, with a Blantyre Coma Score ≤ 2, in this prospective observational study. Children were screened for malaria severity signs and assessed using a systematic diagnostic protocol, including blood cultures, malaria diagnostics, and cerebrospinal fluid analysis using multiplex PCR. To determine factors associated with death, univariate and multivariate analyses were performed. Results From 3244 admissions, 84 children were included: malaria was diagnosed in 78, eight of whom had a viral or bacterial co-infection. Six children had a non-malarial infection or no identified cause. The mortality rate was 29.8% (25/84), with 20 children dying in the first 24 h. Co-infected children appeared to have a poorer prognosis. Of the 76 children who consulted a healthcare professional before admission, only 5 were prescribed adequate antimalarial oral therapy. Predictors of early death were jaundice or increased bilirubin [odd ratio (OR)= 8.6; 95% confidential interval (CI): 2.03–36.1] and lactate > 5 mmol/L (OR = 5.1; 95% CI: 1.49–17.30). Antibiotic use before admission (OR = 0.1; 95% CI: 0.02–0.85) and vaccination against yellow fever (OR = 0.2, 95% CI: 0.05–0.79) protected against mortality. Conclusions Infections were found in all children who died, and cerebral malaria was by far the most common cause of non-traumatic coma. Missed opportunities to receive early effective antimalarial treatment were common. Other central nervous system infections must be considered in their management. Some factors that proved to be protective against early death were unexpected.

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“…falciparum mono-infection were considered. The recruitment of samples has been detailed previously (16) (17).…”

Section: Discussionmentioning

confidence: 99%

“…The present work is part of the NeuroCM study, investigating host and parasite factors leading to neuroinflammation in CM. For this purpose, children presenting with CM and uncomplicated malaria (UM) were recruited in Benin in 2018, during the malaria transmission season (16). A first comparative study (17) highlighted that CM isolates display a greater adherence to Hbec-5i and CHO-ICAM-1 cell lines than UM.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of Plasmodium falciparum isolates from Benin reveals specific gene expression associated with cerebral malaria

Guillochon

Fraering

Joste

et al. 2021

Preprint

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The host and parasitic factors leading to cerebral malaria (CM) are not yet fully elucidated and CM Plasmodium falciparum isolates transcriptome profile remains largely unknown. Based on RNA-seq data from 15 CM and 15 uncomplicated malaria (UM) children from Benin, we identified an increased ring stage signature in CM parasites. Reduced circulating time may result from a higher adherence ability of CM isolates and consistent with this hypothesis, we measured an overexpression of var genes in CM. var genes domains expression was more restricted in CM isolates compared to UM, reflecting the specific binding to receptors in host brain endothelium capillaries. However, ICAM-1 binding motif was found expressed in both CM and UM, questioning its role in PfEMP1 adhesion to ICAM-1 receptor. UM isolates increased circulation time may also be modulated by a more efficient immune response against infected erythrocytes surface proteins, which we could not demonstrate on our cohort. Identification of deregulated genes involved in adhesion, excluding variant surface antigens, also supports the hypothesis of an increased CM adhesion capacity. Finally, numerous upregulated genes involved in entry into host pathway were found, reflecting a greater erythrocytes invasion capacity of CM parasites.

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Identification of Plasmodium falciparum and host factors associated with cerebral malaria: description of the protocol for a prospective, case-control study in Benin (NeuroCM)

Cited by 10 publications

References 36 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

Non-traumatic coma in young children in Benin: are viral and bacterial infections gaining ground on cerebral malaria?

Transcriptome analysis of Plasmodium falciparum isolates from Benin reveals specific gene expression associated with cerebral malaria

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