Abstract
The basis of severe malaria pathogenesis in part includes sequestration of Plasmodium falciparum-infected erythrocytes (IE) from the peripheral circulation. This phenomenon is mediated by the interaction between several endothelial receptors and one of the main parasite-derived variant antigens (PfEMP1) expressed on the surface of the infected erythrocyte membrane. One of the commonly used host receptors is ICAM-1, and it has been suggested that ICAM-1 has a role in cerebral malaria pathology, although the evidence to support this is not conclusive. The current study examined the cytoadherence patterns of lab-adapted patient isolates after selecting on ICAM-1. We investigated the binding phenotypes using variant ICAM-1 proteins including ICAM-1Ref, ICAM-1Kilifi, ICAM-1S22/A, ICAM-1L42/A and ICAM-1L44/A using static assays. The study also examined ICAM-1 blocking by four anti-ICAM-1 monoclonal antibodies (mAb) under static conditions. We also characterised the binding phenotypes using Human Dermal Microvascular Endothelial Cells (HDMEC) under flow conditions. The results show that different isolates have variant-specific binding phenotypes under both static and flow conditions, extending our previous observations that this variation might be due to variable contact residues on ICAM-1 being used by different parasite PfEMP1 variants.
Highlights
Malaria is still a life-threatening disease despite the huge effort to eliminate it
ItG was previously defined as a high-avidity ICAM-1 binder whereas, A4 was characterised as low-avidity ICAM-1 binder from an earlier study [49]
Binding to mutant ICAM-1 proteins The current study showed that there were considerable differences in infected erythrocytes (IE) binding to mutant ICAM-1 proteins (Figure 1)
Summary
Malaria is still a life-threatening disease despite the huge effort to eliminate it. Malaria severe disease syndromes such as cerebral malaria (CM) are thought to involve the adhesion between the parasite derived antigens and a subset of host receptors [2]. The mature stages of the asexual intraerythrocytic cycle of Plasmodium falciparum are not found in the circulation due to their ability to localise to different organs in a phenomenon known as sequestration. Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) [4,5,6] mediates sequestration with various human receptors [3] including ICAM-1 [7] and CD36 [8,9] and EPCR [10]
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