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Defining species-specific and conserved interactions of apical membrane protein 1 during erythrocyte invasion in malaria to inform multi-species vaccines.
Drew, Damien R; Wilson, Danny W; Weiss, Gretchen E; Yeoh, Lee M; G Henshall, Isabelle; Crabb, Brendan S; Dutta, Sheetij; Gilson, Paul R; Beeson, James G.
Affiliation
  • Drew DR; Burnet Institute, 85 Commercial Road, Melbourne, VIC, 3004, Australia.
  • Wilson DW; Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.
  • Weiss GE; Burnet Institute, 85 Commercial Road, Melbourne, VIC, 3004, Australia.
  • Yeoh LM; Burnet Institute, 85 Commercial Road, Melbourne, VIC, 3004, Australia.
  • G Henshall I; Departments of Medicine, Microbiology and Immunology, and Infectious Diseases, The University of Melbourne, Melbourne, 3010, Australia.
  • Crabb BS; Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.
  • Dutta S; Burnet Institute, 85 Commercial Road, Melbourne, VIC, 3004, Australia.
  • Gilson PR; Departments of Medicine, Microbiology and Immunology, and Infectious Diseases, The University of Melbourne, Melbourne, 3010, Australia.
  • Beeson JG; Central Clinical School and Department of Microbiology, Monash University, Victoria, Australia.
Cell Mol Life Sci ; 80(3): 74, 2023 Feb 27.
Article in En | MEDLINE | ID: mdl-36847896
ABSTRACT
Plasmodium falciparum and P. vivax are the major causes of human malaria, and P. knowlesi is an important additional cause in SE Asia. Binding of apical membrane antigen 1 (AMA1) to rhoptry neck protein 2 (RON2) was thought to be essential for merozoite invasion of erythrocytes by Plasmodium spp. Our findings reveal that P. falciparum and P. vivax have diverged and show species-specific binding of AMA1 to RON2, determined by a ß-hairpin loop in RON2 and specific residues in AMA1 Loop1E. In contrast, cross-species binding of AMA1 to RON2 is retained between P. vivax and P. knowlesi. Mutation of specific amino acids in AMA1 Loop1E in P. falciparum or P. vivax ablated RON2 binding without impacting erythrocyte invasion. This indicates that the AMA1-RON2-loop interaction is not essential for invasion and additional AMA1 interactions are involved. Mutations in AMA1 that disrupt RON2 binding also enable escape of invasion inhibitory antibodies. Therefore, vaccines and therapeutics will need to be broader than targeting only the AMA1-RON2 interaction. Antibodies targeting AMA1 domain 3 had greater invasion-inhibitory activity when RON2-loop binding was ablated, suggesting this domain is a promising additional target for vaccine development. Targeting multiple AMA1 interactions involved in invasion may enable vaccines that generate more potent inhibitory antibodies and address the capacity for immune evasion. Findings on specific residues for invasion function and species divergence and conservation can inform novel vaccines and therapeutics against malaria caused by three species, including the potential for cross-species vaccines.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protozoan Proteins / Erythrocytes / Malaria / Membrane Proteins Limits: Humans Language: En Journal: Cell Mol Life Sci Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Affiliation country: Australia

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protozoan Proteins / Erythrocytes / Malaria / Membrane Proteins Limits: Humans Language: En Journal: Cell Mol Life Sci Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Affiliation country: Australia