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Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria
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Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria
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Journal Article
Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria
2017
Overview
Background
Expression of group A and the A-like subset of group B
Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1) is associated with severe malaria (SM). The diversity of
var
sequences combined with the challenges of distinct classification of patient pathologies has made studying the role of distinct PfEMP1 variants on malaria disease severity challenging. The application of retinopathy in the recent years has provided a further method to clinically evaluate children with cerebral malaria (CM). The question of whether children with clinical CM but no retinopathy represent a completely different disease process or a subgroup within the spectrum of CM remains an important question in malaria. In the current study, we use newly designed primer sets with the best coverage to date in a large cohort of children with SM to determine the role of
var
genes in malaria disease severity and especially CM as discriminated by retinopathy.
Methods
We performed qRT-PCR targeting the different subsets of these
var
genes on samples from Ugandan children with CM (
n
= 98, of whom 50 had malarial retinopathy [RP] and 47 did not [RN]), severe malarial anemia (SMA,
n
= 47), and asymptomatic parasitemia (AP,
n
= 14). The primers used in this study were designed based on
var
sequences from 226 Illumina whole genome sequenced
P. falciparum
field isolates.
Results
Increasing severity of illness was associated with increasing levels of endothelial protein C receptor (EPCR)-binding PfEMP1. EPCR-binding PfEMP1 transcript levels were highest in children with combined CM and SMA and then decreased by level of disease severity: RP CM > RN CM > SMA > AP.
Conclusions
The study findings indicate that PfEMP1 binding to EPCR is important in the pathogenesis of SM, including RN CM, and suggest that increased expression of EPCR-binding PfEMP1 is associated with progressively more severe disease. Agents that block EPCR-binding of PfEMP1 could provide novel interventions to prevent or decrease disease severity in malaria.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Child
/ Coma
/ Endothelial Protein C Receptor - metabolism
/ Female
/ Humans
/ Infant
/ Malaria
/ Malaria, Cerebral - metabolism
/ Malaria, Falciparum - metabolism
/ Malaria, Falciparum - pathology
/ Male
/ Medicine
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - immunology
/ Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)
/ Proteins
/ Protozoan Proteins - metabolism
/ Real-Time Polymerase Chain Reaction
/ Retinal Diseases - metabolism
