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BMC Med. 2017 Oct 13;15(1):183. doi: 10.1186/s12916-017-0945-y.

Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria.

Author information

1
Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University, 1044 W Walnut St R4 402D, Indianapolis, Indiana, USA.
2
Department of Pediatrics, Division of Global Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
3
Children's National Medical Center, Washington, DC, USA.
4
Department of Pediatrics and Child Health, Makerere University School of Medicine, Kampala, Uganda.
5
Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen, Denmark.
6
Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University, 1044 W Walnut St R4 402D, Indianapolis, Indiana, USA. chjohn@iu.edu.
7
Department of Pediatrics, Division of Global Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. chjohn@iu.edu.

Abstract

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.

KEYWORDS:

Cerebral malaria; Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1); Retinopathy; Severe malaria; Transcript levels

PMID:
29025399
PMCID:
PMC5639490
DOI:
10.1186/s12916-017-0945-y
[Indexed for MEDLINE]
Free PMC Article

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