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.
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Common virulence gene expression in adult first-time infected malaria patients and severe cases
eLife 10:e69040.
https://doi.org/10.7554/eLife.69040
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Candida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophages with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects fluconazole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata’s survival in macrophages and drug tolerance.
