Common virulence gene expression in adult first-time infected malaria patients and severe cases
- Bernhard Nocht Institute for Tropical Medicine, Germany
- Wellcome Sanger Institute, United Kingdom
- Bernhard Nocht Institute for Tropical Medicine & University Medical Center Hamburg-Eppendorf, Germany
- GEOMAR Helmholtz Centre for Ocean Research Kiel, Germany
- Centre for Medical Parasitology at the University of Copenhagen, Denmark
- University of Tuebingen, Germany
- University of Copenhagen, Denmark
- Bernhard Noch Institute for Tropical Medicine, Germany
Abstract
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.
Data availability
Sequencing data have been deposited at NCBI under the BioProject accession number PRJNA679547.
Article and author information
Author details
Jan Stephan Wichers
Freia-Raphaella Lorenz
Funding
Deutsche Forschungsgemeinschaft (BA5213/3-1)
- Jan Stephan Wichers
- Anna Bachmann
Lundbeckfonden (R344-2020-934)
- Rasmus Weisel Jensen
- Louise Turner
- Thomas Lavstsen
Danish Council for Independent Research
- Rasmus Weisel Jensen
- Louise Turner
- Thomas Lavstsen
Deutsches Zentrum für Infektionsforschung (TTU Malaria)
- Ralf Krumkamp
- Egbert Tannich
- Rolf Fendel
- Anna Bachmann
Partnership of University of Hamburg and DESY (PIF-2018-87)
- Jan Strauss
- Tim Wolf Gilberger
State Graduate Funding Program Scholarship of the University of Hamburg
- Judith Anna Marie Scholz
National Health and Medical Research Council
- Michael Duffy
Wellcome Trust (104111/Z/14/ZR)
- Thomas D. Otto
Kirsten og Freddy Johansens Fond
- Rasmus Weisel Jensen
- Louise Turner
- Thomas Lavstsen
Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat
- Rasmus Weisel Jensen
- Louise Turner
- Thomas Lavstsen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was conducted according to the principles of the Declaration of Helsinki in its 6th revision as well as International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines. Blood samples for this analysis were collected after patients were informed about the aims and risks of the study and signed an informed consent form for voluntary blood draw (n=21). In the remaining cases, no designated blood samples were drawn, instead remains from diag-nostic blood samples were used (n=11). The study was approved by the relevant ethics committee (Ethical Review Board of the Medical Association of Hamburg, reference numbers PV3828 and PV4539).
Copyright
© 2021, Wichers et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,393
- views
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Common virulence gene expression in adult first-time infected malaria patients and severe cases
eLife 10:e69040.
https://doi.org/10.7554/eLife.69040
Further reading
-
- Microbiology and Infectious Disease
eLife has recently published a wide range of papers on malaria, covering a diversity of themes including parasite biology, epidemiology, immunology, drugs and vaccines.
-
- Chromosomes and Gene Expression
- Evolutionary Biology
Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.
