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Published on: January 3, 2012
Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature
Michael Dörpinghaus1, Finn Fürstenwerth1, Lisa K Roth1
1Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
Abstract:
Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.
Insights
Feverish conditions enhance malaria parasite binding to host cells by increasing PfEMP1 expression and promoting the formation of knobs on infected erythrocytes, crucial for survival.
Area of Science:
- Malariology
- Cellular and Molecular Biology
- Immunology
Background:
- Plasmodium falciparum infection alters erythrocyte membranes, enabling cytoadhesion to endothelium.
- Cytoadhesion is mediated by PfEMP1 proteins, encoded by var genes, and linked to severe malaria complications.
- Fever is a common malaria symptom, potentially influencing parasite-host interactions.
Purpose of the Study:
- To investigate the impact of febrile temperatures (40 °C vs. 37 °C) on the cytoadhesion of Plasmodium falciparum-infected erythrocytes (IEs).
- To examine the binding of predominantly knobless IEs to chondroitin-4-sulfate A (CSA), ICAM-1, and CD36 under simulated febrile conditions.
- To understand the role of knobs in IE survival and cytoadhesion during malaria infection, particularly during fever episodes.
Main Methods:
- Enrichment of IEs for binding to CSA, ICAM-1, and CD36 at 40 °C and 37 °C.
- Analysis of var2csa expression and PfEMP1 trafficking to the IE surface.
- Comparison of knob-positive and knobless IE selection under different binding conditions and temperatures.
Main Results:
- IEs binding to CSA at 40 °C showed significantly increased binding capacity compared to those at 37 °C.
- Increased var2csa expression and PfEMP1 surface trafficking were observed at 40 °C for CSA binding.
- Enrichment on ICAM-1 at 40 °C selected for knobby IEs, while CD36 enrichment showed no selection.
- Fever conditions favor the selection of knobby IEs, enhancing parasitic survival.
Conclusions:
- Knobs on infected erythrocytes are critical for parasite survival in the host, especially during fever.
- Febrile conditions exert selection pressure favoring the formation of knobs on infected erythrocytes.
- Host control over knob formation could be a potential therapeutic strategy against malaria.
