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PreprintCited by 17Malaria Research and ControlAdvanced Electron Microscopy Techniques and ApplicationsBird parasitology and diseases

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Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

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Dietrich, Melanie H., Chmielewski, Jill, Chan, Li-Jin, Tan, Li Lynn, Adair, Amy, Lyons, Frankie M. T., Gabriela, Mikha, Lopaticki, Sash, Dite, Toby A, Dagley, Laura F, Pazzagli, Lucia, Gupta, Priya, Kamil, Mohd, Vaughan, Ashley M., Rojrung, Rattanaporn, Abraham, Anju, Mazhari, Ramin, Longley, Rhea J., Zeglinski, Kathleen, Gouil, Quentin, Mueller, Ivo, Fabb, Stewart A., Shandre-Mugan, Rekha, Pouton, Colin W., Glukhova, Alisa, Shakeel, Shabih, Tham, Wai-Hong·2025·Science
DOI 10.1101/2025.02.13.638205

Preprint — published as 10.1126/science.ady0241 · Paper page

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Abstract

Summary: Plasmodium falciparum Pfs230 and Pfs48/45, part of a core fertilization complex, are leading malaria transmission-blocking vaccine candidates. However, how the two proteins interact is unknown. Here we report a 3.36 Å resolution cryo-electron microscopy structure of the endogenous Pfs230-Pfs48/45 complex. We show that Pfs48/45 interacts with Pfs230 domains 13 and 14, domains that are not included in current Pfs230 vaccine immunogens. Using a transgenic parasite line with a domain 13 to 14 deletion, we show that these domains are essential for Pfs230 localization on the gamete surface. Furthermore, this line significantly reduced oocyst formation in the mosquito midgut, showing that the presence of Pfs230 domains 13 and 14 is critical for successful fertilization. Nanobodies against domains 13 and 14 inhibit Pfs230-Pfs48/45 complex formation, reduce transmission and structural analyses reveal their binding epitopes. Furthermore, domains 13 and 14 are targets of naturally acquired immunity and when delivered as mRNA-LNP immunizations induce potent immune responses and blocked transmission of malaria parasites. Our comprehensive structural insights on a core P. falciparum fertilization complex will guide the design of novel transmission-blocking vaccine candidates against malaria.

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Metadata

Authors
Dietrich, M. H., Chmielewski, J., Chan, L.-J., Tan, L. L., Adair, A., Lyons, F. M. T., Gabriela, M., Lopaticki, S., Dite, T. A., Dagley, L. F., Pazzagli, L., Gupta, P., Kamil, M., Vaughan, A. M., Rojrung, R., Abraham, A., Mazhari, R., Longley, R. J., Zeglinski, K., Gouil, Q., Mueller, I., Fabb, S. A., Shandre-Mugan, R., Pouton, C. W., Glukhova, A., Shakeel, S., & Tham, W.-H.
Affiliations
  • The University of Melbourne (AU)
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • Seattle Children's Research Institute (US)
  • University of Washington (US)
  • Ehime University (JP)
  • Monash University (AU)
  • Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
  • Australian National University (AU)
Corresponding author
Tham, Wai-Hong
ORCID
Venue
Science
Publisher
openRxiv
Published
2025-02-14
Volume
389
Issue
6765
Pages
eady0241-eady0241
ISSN
0036-8075 (ISSN-L)
DOI
10.1101/2025.02.13.638205
OpenAlex
W4412794604
Cited by
17
References
1
Citations by year
2026: 12 · 2025: 5
FWCI
15.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • ANU Open Research (Australian National University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Immunology and Microbiology › Parasitology › Bird parasitology and diseases
Keywords
Plasmodium falciparum, Pfs230, Pfs48/45, mosquito midgut, oocyst formation, malaria transmission blocking, nanobodies, epitope mapping, naturally acquired immunity
MeSH terms
Protein Domains, Animals, Anopheles, Antibodies, Protozoan, Epitopes, Antigens, Protozoan, Female, Fertilization, Immune Sera, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Plasmodium falciparum, Protozoan Proteins, Malaria, Falciparum, Cryoelectron Microscopy, Oocysts, Mice, Nanoparticles

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