title: An inhibitory antibody blocks interactions between components of the malarial invasion machinery.
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.
authors.affiliation: Division of Parasitology, National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Collins
authors.forename: Chrislaine
authors.initials: C
authors.lastname: Withers-Martinez
authors.forename: Fiona
authors.initials: F
authors.lastname: Hackett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000502:physiology; D008288:Malaria / Q000276:immunology; D017780:Malaria Vaccines / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity*; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity*; D014443:Tyrosine / Q000502:physiology
chemical_list: C506564:AMA1 protein, Toxoplasma gondii; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D014443:Tyrosine