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

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, John M. Kelly, Lea Barfod and Ivan Campeotto ()
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Sagar Batra: Sutton Bonington Campus
Francisco Olmo: University of Granada
Timothy J. Ragan: University of Leicester
Merve Kaplan: University of Oxford
Valeria Calvaresi: 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
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects.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.

Date: 2025
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DOI: 10.1038/s41467-025-62068-3

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