Abstract
Host cell invasion by apicomplexan pathogens such as the malaria parasite Plasmodium spp. and Toxoplasma gondii involves discharge of proteins from secretory organelles called micronemes and rhoptries. In Toxoplasma a protein complex comprising the microneme apical membrane antigen 1 (AMA1), two rhoptry neck proteins, and a protein called Ts4705, localises to the moving junction, a region of close apposition between parasite and host cell during invasion. Antibodies against AMA1 prevent invasion and are protective in vivo, and so AMA1 is of widespread interest as a malaria vaccine candidate. Here we report that the AMA1 complex identified in Toxoplasma is conserved in Plasmodium falciparum. We demonstrate that the invasion-inhibitory monoclonal antibody (mAb) 4G2, which recognises P. falciparum AMA1 (PfAMA1), cannot bind when PfAMA1 is in a complex with its partner proteins. We further show that a single completely conserved PfAMA1 residue, Tyr251, lying within a conserved hydrophobic groove adjacent to the mAb 4G2 epitope, is required for complex formation. We propose that mAb 4G2 inhibits invasion by preventing PfAMA1 from interacting with other components of the invasion complex. Our findings should aid the rational design of subunit malaria vaccines based on PfAMA1.
Highlights
Malaria is a global problem, affecting many of the world’s poorest nations
P. falciparum AMA1 (PfAMA1) forms a complex with three AMA1associated proteins (AAPs) In both Toxoplasma and Plasmodium, apical membrane antigen 1 (AMA1) interacts with the rhoptry neck protein RON4 [12,13,14]
Two rounds of depletion with monoclonal antibody (mAb) 4G2 precipitated free PfAMA1 but did not result in any AAP co-precipitation, whereas subsequent IP with either N5 or mAb 24C6 precipitated the PfAMA1-AAP complex. These results indicate that mAb 4G2 does not destabilise the PfAMA1-AAP complex, but cannot bind it
Summary
Malaria is a global problem, affecting many of the world’s poorest nations. Around 40% of the world’s population is at risk from the disease with over 500 million clinical cases yearly, and malaria is a major cause of mortality in children under five. Malaria is caused by protozoan parasites of the genus Plasmodium, with the most severe disease being the result of infection with P. falciparum. The malaria merozoite invades erythrocytes and undergoes rounds of asexual replication (schizogony) to generate a schizont containing multiple daughter merozoites. The merozoites are released to invade new erythrocytes. Repetitive cycles of invasion, replication and schizont rupture are responsible for the clinical symptoms of the disease. The development of a malaria vaccine and the identification of new parasite targets for chemotherapeutic intervention are important ways forward in combating the disease
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