Towards an anti-disease malaria vaccine

Abstract

Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

Keywords: malaria; surface protein; vaccine.

Figure 1.. The molecular basis for binding of PfEMP1 associated with severe disease to human receptors.

(A) The architecture of PfEMP1 ectodomains displayed on the surface of erythrocytes infected with P. falciparum. Classical PfEMP1s are rigid and elongated in structure [51], whereas VAR2CSA is the only PfEMP1 known to have an overall globular structure [52]. The two domain types in PfEMP1, CIDR domains (yellow) and DBL domains (green), are indicated. (B) Crystal structure of a CIDR domain (yellow) bound to its human receptor, EPCR (blue). The inset shows the CIDR residues (red) that make direct contact with EPCR and their conservation across 737 EPCR-binding CIDR domains, displayed as a sequence logo [36]. (C) Crystal structure of a DBL domain (green) bound to the first two domains of its human receptor, ICAM-1 (blue). The inset shows the DBL residues (red) that directly contact ICAM-1 and a sequence logo showing their conservation across 145 ICAM-1-binding DBL domains [38].