A broadly cross-reactive i-body to AMA1 potently inhibits blood and liver stages of Plasmodium parasites.

Autor: Angage D; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Chmielewski J; Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia., Maddumage JC; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Hesping E; Infectious Diseases & Immune Defense Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia., Caiazzo S; Infectious Diseases & Immune Defense Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia., Lai KH; Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia., Yeoh LM; Burnet Institute, Melbourne, Victoria, 3004, Australia.; Department of Medicine, The University of Melbourne, Parkville, Victoria, 3052, Australia., Menassa J; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Opi DH; Burnet Institute, Melbourne, Victoria, 3004, Australia.; Department of Medicine, The University of Melbourne, Parkville, Victoria, 3052, Australia.; Central Clinical School and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia., Cairns C; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Puthalakath H; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Beeson JG; Burnet Institute, Melbourne, Victoria, 3004, Australia.; Central Clinical School and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.; Department of Infectious Diseases, The University of Melbourne, Parkville, Victoria, 3052, Australia., Kvansakul M; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Boddey JA; Infectious Diseases & Immune Defense Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3052, Australia., Wilson DW; Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia.; Burnet Institute, Melbourne, Victoria, 3004, Australia.; Institute for Photonics and Advanced Sensing (IPAS), University of Adelaide, Adelaide, South Australia, 5005, Australia., Anders RF; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia., Foley M; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Victoria, 3086, Australia. m.foley@latrobe.edu.au.; AdAlta, Science Drive, Bundoora, Victoria, 3083, Australia. m.foley@latrobe.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 22; Vol. 15 (1), pp. 7206. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1038/s41467-024-50770-7
Abstrakt: Apical membrane antigen-1 (AMA1) is a conserved malarial vaccine candidate essential for the formation of tight junctions with the rhoptry neck protein (RON) complex, enabling Plasmodium parasites to invade human erythrocytes, hepatocytes, and mosquito salivary glands. Despite its critical role, extensive surface polymorphisms in AMA1 have led to strain-specific protection, limiting the success of AMA1-based interventions beyond initial clinical trials. Here, we identify an i-body, a humanised single-domain antibody-like molecule that recognises a conserved pan-species conformational epitope in AMA1 with low nanomolar affinity and inhibits the binding of the RON2 ligand to AMA1. Structural characterisation indicates that the WD34 i-body epitope spans the centre of the conserved hydrophobic cleft in AMA1, where interacting residues are highly conserved among all Plasmodium species. Furthermore, we show that WD34 inhibits merozoite invasion of erythrocytes by multiple Plasmodium species and hepatocyte invasion by P. falciparum sporozoites. Despite a short half-life in mouse serum, we demonstrate that WD34 transiently suppressed P. berghei infections in female BALB/c mice. Our work describes the first pan-species AMA1 biologic with inhibitory activity against multiple life-cycle stages of Plasmodium. With improved pharmacokinetic characteristics, WD34 could be a potential immunotherapy against multiple species of Plasmodium.
(© 2024. The Author(s).)
Databáze: MEDLINE
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