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Differential PfEMP1 expression is associated with cerebral malaria pathology
Dumizulu L Tembo1, Benjamin Nyoni2, Rekah V Murikoli2
1Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Abstract:
Plasmodium falciparum is unique among human malarias in its ability to sequester in post-capillary venules of host organs. The main variant antigens implicated are the P. falciparum erythrocyte membrane protein 1 (PfEMP1), which can be divided into three major groups (A-C). Our study was a unique examination of sequestered populations of parasites for genetic background and expression of PfEMP1 groups. We collected post-mortem tissue from twenty paediatric hosts with pathologically different forms of cerebral malaria (CM1 and CM2) and parasitaemic controls (PC) to directly examine sequestered populations of parasites in the brain, heart and gut. Use of two different techniques to investigate this question produced divergent results. By quantitative PCR, group A var genes were upregulated in all three organs of CM2 and PC cases. In contrast, in CM1 infections displaying high levels of sequestration but negligible vascular pathology, there was high expression of group B var. Cloning and sequencing of var transcript tags from the same samples indicated a uniformly low expression of group A-like var. Generally, within an organ sample, 1-2 sequences were expressed at dominant levels. 23% of var tags were detected in multiple patients despite the P. falciparum infections being genetically distinct, and two tags were observed in up to seven hosts each with high expression in the brains of 3-4 patients. This study is a novel examination of the sequestered parasites responsible for fatal cerebral malaria and describes expression patterns of the major cytoadherence ligand in three organ-derived populations and three pathological states.
Insights
Plasmodium falciparum sequestration in organs involves P. falciparum erythrocyte membrane protein 1 (PfEMP1). Group B var genes were highly expressed in non-pathological cerebral malaria, while Group A var genes were upregulated in severe cases.
Area of Science:
- Malariology
- Immunology
- Genetics
Background:
- Plasmodium falciparum uniquely sequesters in post-capillary venules.
- P. falciparum erythrocyte membrane protein 1 (PfEMP1) mediates cytoadherence and is divided into groups A-C.
- Cerebral malaria (CM) involves parasite sequestration in vital organs.
Purpose of the Study:
- To investigate the genetic background and PfEMP1 group expression in sequestered P. falciparum populations.
- To compare parasite expression patterns across different cerebral malaria pathologies (CM1, CM2) and parasitaemic controls (PC).
- To analyze sequestered parasite populations directly from post-mortem brain, heart, and gut tissues.
Main Methods:
- Post-mortem tissue collection from twenty paediatric patients with CM1, CM2, and PC.
- Quantitative PCR to assess var gene group expression.
- Cloning and sequencing of var transcript tags to identify dominant expressed sequences.
Main Results:
- Quantitative PCR showed Group A var genes upregulated in CM2 and PC cases across organs.
- CM1 infections exhibited high Group B var expression, correlating with sequestration but not vascular pathology.
- Cloning and sequencing revealed low Group A-like var expression, with dominant expression of 1-2 sequences per sample.
- 23% of var tags were found in multiple genetically distinct patients, with two tags appearing in up to seven hosts.
Conclusions:
- Parasite sequestration and PfEMP1 expression vary significantly with cerebral malaria pathology.
- Specific var gene groups (A and B) are differentially expressed depending on the clinical presentation of cerebral malaria.
- A subset of PfEMP1 variants may be broadly expressed across genetically distinct P. falciparum infections, suggesting potential roles in severe malaria pathogenesis.
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