Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection

Obeng-Adjei, Nyamekye; Larremore, Daniel B.; Turner, Louise; Ongoïba, Aïssata; Li, Shanping; Doumbo, Safiatou; Yazew, Takele; Kayentao, Kassoum; Miller, Louis H.; Traoré, Boubacar; Buckee, Caroline O.; Lavstsen, Thomas; Crompton, Peter D.; Tran, Tuan M.

doi:10.1172/jci.insight.137262

Cited by 26 publications

(28 citation statements)

References 61 publications

(73 reference statements)

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“…However, together with previous observations, our data suggest that paediatric cerebral malaria infections are dominated by the expansion of parasites expressing EPCR-binding domains accompanied by parasites expressing other group A Pf EMP1, possibly acting as rosetting variants. This was consistent with the more frequent recognition of CIDRα1 domains than CIDRα2–6 domains in pre-exposed patients, indicating that IgG against EPCR-binding CIDR domains were acquired before IgG to other CIDR domains, as has been observed for malaria endemic populations ( Obeng-Adjei et al, 2020 ; Cham et al, 2009 ; Cham et al, 2010 ; Turner et al, 2015 ).…”

Section: Discussionsupporting

confidence: 85%

“…A detailed analysis of the antibody repertoire of the patients against head structure CIDR domains of Pf EMP1 was carried out using a panel of 19 different EPCR-binding CIDRα1 domains, 12 CD36-binding CIDRα2–6 domains, three CIDRδ1 domains as well as a single CIDRγ3 domain ( Obeng-Adjei et al, 2020 ; Bachmann et al, 2019 ). Additionally, the minimal binding region of VAR2CSA was included.…”

Section: Resultsmentioning

confidence: 99%

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Common virulence gene expression in adult first-time infected malaria patients and severe cases

Wichers

Tonkin‐Hill

Thye

et al. 2021

eLife

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Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naïve immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Common virulence gene expression in adult first-time infected malaria patients and severe cases

Wichers

Tonkin‐Hill

Thye

et al. 2021

eLife

Self Cite

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show abstract

“…However, together with previous observations our data suggest that pediatric cerebral malaria infections are dominated by the expansion of parasites expressing EPCR-binding domains accompanied by parasites expressing other group A Pf EMP1, possibly acting as rosetting variants. This was consistent with pre-exposed patients more frequent recognition of CIDRα1 domains than CIDRα2-6 domains, indicating that IgG against EPCR-binding CIDR domains were acquired before IgG to other CIDR domains, as has been observed for malaria endemic populations (Obeng-Adjei et al , 2020; Cham et al , 2009, 2010; Turner et al , 2015).…”

Section: Discussionsupporting

confidence: 85%

“…A detailed analysis of the antibody repertoire of the patients against head structure CIDR domains of Pf EMP1 was carried out using a panel of 19 different EPCR-binding CIDRα1 domains, 12 CD36-binding CIDRα2-6 domains, three CIDRδ1 domains as well as a single CIDRγ3 domain (Obeng-Adjei et al, 2020; Bachmann et al, 2019). Additionally, the minimal binding region of VAR2CSA was included (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

“…This is in agreement with studies from malaria endemic setting indicating that IgG against EPCR-binding domains were acquired first followed by domains with unknown binding phenotypes associated with rosetting and CD36-binding domains. Resulting in the earlier acquisition of antibodies against DBL and CIDR domains of group A and B/A, associated with EPCR binding, than against B- and C-type domains (Obeng-Adjei et al, 2020; Cham et al, 2009, 2010; Turner et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

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Gene expression profiling of malaria parasites reveals common virulence gene expression in adult first-time infected patients and severe cases

Wichers

Tonkin‐Hill

Thye

et al. 2020

Preprint

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Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins, is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring the same array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 infected travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. Expression analysis of PfEMP1-encoding var genes showed that severe malaria was associated with expression of PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. In addition, gene expression-guided determination of parasite age, suggested that circulating parasites from non-severe malaria patients were older than parasites from severe malaria patients. First-time infected patients were also more likely to develop severe symptoms and tended to be infected for a longer period, which thus appeared to select for parasites with more sequestration-efficiency and therefore more pathogenic PfEMP1 variants.

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Production of anti-PfEMP1 Polyclonal Antisera in Rats and Mice

Olsen

Suurbaar

Jensen

2022

Methods in Molecular Biology

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Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection

Cited by 26 publications

References 61 publications

Common virulence gene expression in adult first-time infected malaria patients and severe cases

Common virulence gene expression in adult first-time infected malaria patients and severe cases

Gene expression profiling of malaria parasites reveals common virulence gene expression in adult first-time infected patients and severe cases

Production of anti-PfEMP1 Polyclonal Antisera in Rats and Mice

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