Abstract
The malaria parasite Plasmodium knowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host’s humoral response to AMA1.
Highlights
Human malaria was long thought to be restricted to infection by four Plasmodium species: P. falciparum, P. vivax, P. malariae and P. ovale
R31C2 was the first invasion-inhibitory anti-Apical Membrane Antigen 1 (AMA1) monoclonal antibody (mAb) to be characterized, providing the first demonstration that AMA1 plays a crucial role in the infection of red blood cell (RBC) by Plasmodium merozoites and highlighting the potential of this parasite protein as a malaria vaccine candidate [6]
P. knowlesi merozoites are able to attach to the RBC surface in the presence of R31C2 but no penetration of the host cell is observed, implying that AMA1 comes into play after initial contact by the parasite [35]
Summary
Human malaria was long thought to be restricted to infection by four Plasmodium species: P. falciparum, P. vivax, P. malariae and P. ovale. It has been confirmed, that natural human infection occurs with P. knowlesi [1], a species hitherto associated only with macaque hosts. Apical Membrane Antigen 1 (AMA1), a type 1 transmembrane protein of the Plasmodium parasite, includes an ectodomain, a transmembrane region and a cytoplasmic domain. In spite of significant polymorphism, it is a leading malaria vaccine candidate and vaccine formulations based on the P. falciparum AMA1 ectodomain are currently being pursued in clinical trials [15, 16]
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