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Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP

Author

Listed:
  • Sagar Batra

    (Sutton Bonington Campus
    School of Science and Technology, Nottingham Trent University)

  • Francisco Olmo

    (University of Granada)

  • Timothy J. Ragan

    (University of Leicester)

  • Merve Kaplan

    (University of Oxford
    University of Oxford)

  • Valeria Calvaresi

    (University of Oxford
    University of Oxford)

  • Asger Meldgaard Frank

    (University of Copenhagen)

  • Claudia Lancey

    (University of Leicester)

  • Mahya Assadipapari

    (Nottingham Trent University)

  • Cuifeng Ying

    (Nottingham Trent University)

  • Weston B. Struwe

    (University of Oxford
    University of Oxford)

  • Emma L. Hesketh

    (University of Leicester)

  • John M. Kelly

    (London School of Hygiene and Tropical Medicine)

  • Lea Barfod

    (University of Copenhagen)

  • Ivan Campeotto

    (Sutton Bonington Campus)

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a significant global public health concern. Despite its profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects. The 80 kDa prolyl oligopeptidase of Trypanosoma cruzi (TcPOP) has been identified as a leading candidate for Chagas vaccine development. Here we report the three-dimensional structure of TcPOP in open and closed conformation, at a global resolution of 3.8 and 3.6 Å, respectively, determined using single-particle cryo-electron microscopy. Multiple conformations were observed and further characterized using plasmonic optical tweezers and hydrogen-deuterium exchange mass spectrometry. To assess the immunogenic potential of TcPOP, we immunized female mice and evaluated both polyclonal and monoclonal responses against the TcPOP antigen and its homologues. The anti-TcPOP polyclonal response demonstrates invasion blocking properties via parasite lysis. Polyclonal sera were cross-reactive with closely-related POPs but not with human homologues. Collectively, our findings provide structural and functional insights necessary to understand the immunogenicity of TcPOP for future Chagas vaccine development.

Suggested Citation

  • Sagar Batra & Francisco Olmo & Timothy J. Ragan & Merve Kaplan & Valeria Calvaresi & Asger Meldgaard Frank & Claudia Lancey & Mahya Assadipapari & Cuifeng Ying & Weston B. Struwe & Emma L. Hesketh & J, 2025. "Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62068-3
    DOI: 10.1038/s41467-025-62068-3
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    References listed on IDEAS

    as
    1. Mark A. Herzik & Mengyu Wu & Gabriel C. Lander, 2019. "High-resolution structure determination of sub-100 kDa complexes using conventional cryo-EM," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. Bruno E. Correia & John T. Bates & Rebecca J. Loomis & Gretchen Baneyx & Chris Carrico & Joseph G. Jardine & Peter Rupert & Colin Correnti & Oleksandr Kalyuzhniy & Vinayak Vittal & Mary J. Connell & E, 2014. "Proof of principle for epitope-focused vaccine design," Nature, Nature, vol. 507(7491), pages 201-206, March.
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