Plasmodium - Host-parasite interaction

Nahla Galal Metwally, Yifan Wu, Susann Ofori, Hanifeh Torabi, Johannes Allweier, Pilar Martinez, Agnes Murk, Milad Temori

P. falciparum is responsible for most of the morbidity and mortality accompanying malaria infections in humans. According to WHO, 216 million cases were reported globally in 2017. Malaria caused 445 000 malaria deaths from which the majority were children under 5 years of age, mainly in Sub-Saharan Africa (WHO, World Malaria Report 2017).

A major virulence determinant for this parasite is attributed to the ability of P. falciparum infected erythrocytes (IEs) to evade the immune system and to adhere in small blood vessels of vital organs most likely the small intestine, heart, lung and brain within its human host. This cytoadhesion of IEs is the major reason for the most severe pathological phenotypes observed in malaria, which include blood flow obstruction, hypoxia, induction of inflammatory immune responses, endothelial dysfunction, tissue damage and, ultimately, organ failure.

The interaction of IEs with host endothelial receptors is mainly mediated by members of the PfEMP1 family. The PfEMP1 encoding var genes vary greatly from parasite to parasite, giving rise to an enormous repertoire of different var genes in nature. Var genes are mutually exclusively expressed in ring-stage parasites, meaning that only one PfEMP1 variant is localized on the surface of IEs at a given time. PfEMP1 molecules consist of a single intracellular and transmembrane domain and several different extracellular domains.

Until now, at least 23 endothelial receptors have been identified to interact with P. falciparum IEs. However, the interactions to only a few of them (CD36, ICAM-1, and EPCR) were studied in detail and the extracellular PfEMP1 domains responsible for adhesion were identified.

Plasmodium infected erythrocytes can cytoadhere to endothelial cells, which is mainly mediated by proteins of the PfEMP1 family. Depending on the location of the binding, cytoadherence can have severe consequences for the human host. If infected erythrocytes bind to endothelial cells in the brain, cerebral malaria (CM) can occur. Nevertheless, cytoadhesion is necessary but not sufficient to explain the severe outcome. The binding of infected erythrocytes to endothelia cells also induced inflammatory response and endothelial dysfunction, which contributes the severity of a CM.

In this project we focus on four major aspects.

• Identification of PfEMP1 ligands/domains mediating cytoadhesion to various receptors
• Characterization of the receptor-ligand phenotypes using a laminar flow system and atomic force microscopy
• Identification of new endothelial receptors involved in cytoadhesion of infected erythrocytes
• The transcriptional changes of human endothelial cells (HBMECs) due to interaction with infected erythrocytes.

Supported by the Jürgen Manchot Stiftung, Joachim Herz Stiftung, Leibniz Center Infection, DZIF.
Collaborator: Tobias Spielmann (BNITM, JC–joint PhD student), Thomas Gutsmann (FZ Borstel)