The Molecular Basis of Erythrocyte Invasion by Malaria Parasites

Abstract

Plasmodium species cause malaria by proliferating in human erythrocytes. Invasion of immunologically privileged erythrocytes provides a relatively protective niche as well as access to a rich source of nutrients. Plasmodium spp. target erythrocytes of different ages, but share a common mechanism of invasion. Specific engagement of erythrocyte receptors defines target cell tropism, activating downstream events and resulting in the physical penetration of the erythrocyte, powered by the parasite's actinomyosin-based motor. Here we review the latest in our understanding of the molecular composition of this highly complex and fascinating biological process.

Engagement Rules That Underpin DBL-DARC Interactions for Ingress of Plasmodium knowlesi and Plasmodium vivax Into Human Erythrocytes

“…Engagements of specific host receptors with parasite-encoded ligands between human erythrocytes and malaria parasite surface proteins are key events in invasion of merozoites into erythrocytes (Cowman et al, 2017). The signature Duffy binding-like domain (DBL) is present in parasite-encoded erythrocyte binding proteins (EBPs) and in protein families like Plasmodium falciparum ( Pf ) erythrocyte membrane protein 1 (EMP1; Cowman et al, 2017).…”

“…The signature Duffy binding-like domain (DBL) is present in parasite-encoded erythrocyte binding proteins (EBPs) and in protein families like Plasmodium falciparum ( Pf ) erythrocyte membrane protein 1 (EMP1; Cowman et al, 2017). The latter are part of the var gene family where they assist in cytoadherence—these contain several copies of DBLs in each protein, whereas the Pf -EBP named EBA-175 harbors two copies (F1 and F2) of DBLs (Mayor et al, 2005; Tolia et al, 2005).…”

“…There are multiple EBPs present in the malaria parasite Pk (α, β, and γ), and it is the Pk α-DBL and Pv -DBL that mediate Duffy antigen receptor for chemokines (DARC)-dependent invasion of erythrocytes in humans (Choe et al, 2005; Hans et al, 2005; Chitnis and Sharma, 2008). Other DBL variants of Pk -EBPs: β and γ likely use alternate receptors on rhesus/human erythrocytes and may mediate invasion by Duffy antigen-independent pathways (Chitnis and Miller, 1994; Cowman et al, 2017). The Pk/Pv -DBLs (as part of their EBPs) are present on merozoite surface and are responsible for binding to the DARC receptor on reticulocytes (Figure 1) and thence mediating junction formation that is vital for the parasite invasion process (Adams et al, 1990, 1992; Cowman and Crabb, 2006; Cowman et al, 2017).…”

“…Other DBL variants of Pk -EBPs: β and γ likely use alternate receptors on rhesus/human erythrocytes and may mediate invasion by Duffy antigen-independent pathways (Chitnis and Miller, 1994; Cowman et al, 2017). The Pk/Pv -DBLs (as part of their EBPs) are present on merozoite surface and are responsible for binding to the DARC receptor on reticulocytes (Figure 1) and thence mediating junction formation that is vital for the parasite invasion process (Adams et al, 1990, 1992; Cowman and Crabb, 2006; Cowman et al, 2017). …”

“…It is a promiscuous cytokine/chemokine receptor involved in pro-inflammatory processes of the immune system (Rot and von Andrian, 2004; Cowman et al, 2017). DARC is also used as an entry vehicle by malaria parasites Pk and Pv (Miller et al, 1975, 1976; Chitnis and Sharma, 2008).…”