Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP
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profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects....
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62068-3 |
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| author | 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 Ivan Campeotto |
| author_facet | 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 Ivan Campeotto |
| author_sort | Sagar Batra |
| collection | DOAJ |
| description | 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profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects.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. |
| format | Article |
| id | doaj-art-d18833fd5c014307bba08095627b513b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d18833fd5c014307bba08095627b513b2025-08-20T04:02:55ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62068-3Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOPSagar Batra0Francisco Olmo1Timothy J. Ragan2Merve Kaplan3Valeria Calvaresi4Asger Meldgaard Frank5Claudia Lancey6Mahya Assadipapari7Cuifeng Ying8Weston B. Struwe9Emma L. Hesketh10John M. Kelly11Lea Barfod12Ivan Campeotto13School of Biosciences, Division of Microbiology, Brewing and Biotechnology, University of Nottingham, Sutton Bonington CampusDepartment of Parasitology, Faculty of Sciences, University of GranadaLeicester Institute of Structural and Chemical Biology, University of LeicesterPhysical and Theoretical Chemistry Laboratory, Department of Chemistry, University of OxfordKavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of OxfordDepartment of Immunology and Microbiology, Centre for Medical Parasitology, Faculty of Health and Medical Sciences, University of CopenhagenLeicester Institute of Structural and Chemical Biology, University of LeicesterAdvanced Optics & Photonics Laboratory, Department of Engineering, School of Science & Technology, Nottingham Trent UniversityAdvanced Optics & Photonics Laboratory, Department of Engineering, School of Science & Technology, Nottingham Trent UniversityKavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of OxfordLeicester Institute of Structural and Chemical Biology, University of LeicesterDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineDepartment of Immunology and Microbiology, Centre for Medical Parasitology, Faculty of Health and Medical Sciences, University of CopenhagenSchool of Biosciences, Division of Microbiology, Brewing and Biotechnology, University of Nottingham, Sutton Bonington CampusAbstract 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.https://doi.org/10.1038/s41467-025-62068-3 |
| spellingShingle | 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 Ivan Campeotto Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP Nature Communications |
| title | Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP |
| title_full | Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP |
| title_fullStr | Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP |
| title_full_unstemmed | Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP |
| title_short | Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP |
| title_sort | cryo em led analysis of open and closed conformations of chagas vaccine candidate tcpop |
| url | https://doi.org/10.1038/s41467-025-62068-3 |
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