Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP
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profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects.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.
Authors
- Cuifeng Ying (ORCID: https://orcid.org/0000-0002-7279-1388)
- Weston B. Struwe (ORCID: https://orcid.org/0000-0003-0594-226X)
- Lea Barfod (ORCID: https://orcid.org/0000-0001-6510-495X)
- Merve Kaplan (ORCID: https://orcid.org/0000-0002-3322-0988)
- Asger Meldgaard Frank (ORCID: https://orcid.org/0000-0002-4097-1413)
- Claudia Lancey (ORCID: https://orcid.org/0000-0001-9064-4085)
- Valeria Calvaresi (ORCID: https://orcid.org/0000-0002-1756-8853)
- Sagar Batra (ORCID: https://orcid.org/0000-0003-3986-5047)
- Timothy J. Ragan (ORCID: https://orcid.org/0000-0002-6233-3375)
- Emma L. Hesketh (ORCID: https://orcid.org/0000-0002-4522-0061)
- Ivan Campeotto (ORCID: https://orcid.org/0000-0002-0814-619X)
- John M. Kelly (ORCID: https://orcid.org/0000-0003-4305-5258)
- Mahya Assadipapari (ORCID: https://orcid.org/0009-0005-0222-5646)
- Francisco Olmo (ORCID: https://orcid.org/0000-0001-9314-0026)
Institutions
- University of Copenhagen (DK)
- University of Nottingham (GB)
- University of Leicester (GB)
- Universidad de Granada (ES)
- University of Oxford (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Nottingham Trent University (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s41467-025-62068-3
- Citations
- 1
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- Wellcome
- London School of Hygiene and Tropical Medicine
- Diamond Light Source
- Royal Society
- University of Leicester
- University of Oxford
- Novo Nordisk
- Universidad de Granada
- Novo Nordisk Fonden
- Medical Research Council