Differences in Gene Transcriptomic Pattern of Plasmodium falciparum in Children with Cerebral Malaria and Asymptomatic Carriers

Almelli, Talleh; Bischoff, Emmanuel; Aubouy, Agnès; Elati, Mohamed; Wang, Christian W.; Dillies, Marie‐Agnès; Coppée, Jean‐Yves; Ayissi, Georges Nko; Basco, Léonardo K.; Rogier, Christophe; Ndam, Nicaise Tuikue; Deloron, Philippe; Tahar, Rachida

doi:10.1371/journal.pone.0114401

Cited by 31 publications

(37 citation statements)

References 59 publications

(67 reference statements)

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“…Cytoadhesion to gC1qR by Mozambican isolates correlated positively with their transcript levels of DC8 which, in line with previous studies [34,42,43], were higher in parasites collected from Mozambican children with severe anemia than in those with UM. Moreover, DC8 was transcribed at higher levels by isolates from individuals with limited antimalarial immunity (i.e., Mozambican children and first-time infected travelers) compared to isolates from Mozambican adults with life-long exposure to malaria.…”

Section: Discussionsupporting

confidence: 89%

Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria

et al. 2016

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Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction.

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Section: Discussionsupporting

confidence: 89%

Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria

et al. 2016

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“…With exception of the short var3 Pf EMP1 variants, A-type Pf EMP1 proteins have an extended, multiple domain composition and a non CD36-binding head structure consisting of a DBLα1 and a CIDRα1/β/γ/δ domain. Their pattern of expression has been linked to severe disease outcome [ 11 – 20 ]. The 37 member group B var genes are located closest to the telomere and transcribed towards the centromere and their expression has been associated with both severe and mild malaria [ 13 , 15 , 19 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

Mosquito Passage Dramatically Changes var Gene Expression in Controlled Human Plasmodium falciparum Infections

et al. 2016

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Virulence of the most deadly malaria parasite Plasmodium falciparum is linked to the variant surface antigen PfEMP1, which is encoded by about 60 var genes per parasite genome. Although the expression of particular variants has been associated with different clinical outcomes, little is known about var gene expression at the onset of infection. By analyzing controlled human malaria infections via quantitative real-time PCR, we show that parasite populations from 18 volunteers expressed virtually identical transcript patterns that were dominated by the subtelomeric var gene group B and, to a lesser extent, group A. Furthermore, major changes in composition and frequency of var gene transcripts were detected between the parental parasite culture that was used to infect mosquitoes and Plasmodia recovered from infected volunteers, suggesting that P. falciparum resets its var gene expression during mosquito passage and starts with the broad expression of a specific subset of var genes when entering the human blood phase.

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“…One of these proteins (124512554-PF08-0091) has also been identified as down regulated from CM isolates in the work of Almelli and al . 15 . Four others are proteins involved in the membrane structure (124505949-skeleton-binding protein 1; 237665420-rhoptry-associated protein 2; 109692347-SNARE protein and 237665024-membrane protein Pf12 precursor).…”

Section: Discussionmentioning

confidence: 99%

“…The gene encoding MAL7P1.171 was also reported as up-regulated in CM in comparison to asymptomatic malaria samples (fold change value 4.46) by Almelli and al . 15 . Similarly, the genes encoding the proteins MAL13P1.295 and PF14_0577 have been shown to be up regulated in CM samples 15 .…”

Section: Discussionmentioning

confidence: 99%

“…It is thus important to validate transcriptomic approaches at the proteomic level. In the case of CM, few studies have investigated the transcriptomic or proteomic pattern of field isolates 14 15 as opposed to PAM where most studies involved such field isolates 16 17 18 . Using a proteomic approach, we compared the expression profiles of parasite proteins located in the infected-erythrocyte membrane or proteins of unknown function that are specific of P. falciparum isolates associated with two distinct clinical presentations of malaria, CM and uncomplicated malaria (UM).…”

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confidence: 99%

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Proteomic analysis of Plasmodium falciparum parasites from patients with cerebral and uncomplicated malaria

Bertin

Sabbagh

Argy

et al. 2016

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Plasmodium falciparum is responsible of severe malaria, including cerebral malaria (CM). During its intra-erythrocytic maturation, parasite-derived proteins are expressed, exported and presented at the infected erythrocyte membrane. To identify new CM-specific parasite membrane proteins, we conducted a mass spectrometry-based proteomic study and compared the protein expression profiles between 9 CM and 10 uncomplicated malaria (UM) samples. Among the 1097 Plasmodium proteins identified, we focused on the 499 membrane-associated and hypothetical proteins for comparative analysis. Filter-based feature selection methods combined with supervised data analysis identified a subset of 29 proteins distinguishing CM and UM samples with high classification accuracy. A hierarchical clustering analysis of these 29 proteins based on the similarity of their expression profiles revealed two clusters of 15 and 14 proteins, respectively under- and over-expressed in CM. Among the over-expressed proteins, the MESA protein is expressed at the erythrocyte membrane, involved in proteins trafficking and in the export of variant surface antigens (VSAs), but without antigenic function. Antigen 332 protein is exported at the erythrocyte, also involved in protein trafficking and in VSAs export, and exposed to the immune system. Our proteomics data demonstrate an association of selected proteins in the pathophysiology of CM.

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Differences in Gene Transcriptomic Pattern of Plasmodium falciparum in Children with Cerebral Malaria and Asymptomatic Carriers

Cited by 31 publications

References 59 publications

Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria

Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria

Mosquito Passage Dramatically Changes var Gene Expression in Controlled Human Plasmodium falciparum Infections

Proteomic analysis of Plasmodium falciparum parasites from patients with cerebral and uncomplicated malaria

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