Specific receptor usage in Plasmodium falciparum cytoadherence is associated with disease outcome

Abstract

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases.

Figure 1. Distribution of clinical samples used in the study.

Scheme showing the collection and classification of infected blood samples from children with different malaria syndromes: uncomplicated (UM), severe malaria other (SM other); cerebral malaria (CM); severe malaria anaemia (SMA). The following symbols designate: * severe malaria but no CM or anaemia; ϕ one patient had an Hb<5g/dl and CM; n = number of clinical samples; low para, low parasitaemia

Figure 2. Mean adhesion of clinical isolates to CD36 and ICAM-1 proteins.

Experiments were performed under static (a) and flow (b) conditions at coating concentrations for CD36 and ICAM-1 proteins of 50 µg/ml. Data represent the mean number of adherent parasites per mm²±standard error. p values that describe significant associations are shown.

Figure 3. Binding signatures for P. falciparum clinical isolates under static conditions.

Binding signatures calculated by comparing ICAM-1^Kilifi and ICAM-1^S22/A clinical binding data against that of ICAM-1^Reference the reference standard. Data was calculated using adhesion to ICAM-1^Reference as a standard against which relative adhesion to ICAM-1 ^Kilifi and ^S22/A are calculated. a, designates strong (80–100%), b, moderate (50–79%) and c, low (0–49%) adhesion. The number of isolates with Severe malaria n = 35 and UM n = 32.