Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine
Abstract Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutan...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58182-x |
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| author | Kalvis Brangulis Jill Malfetano Ashley L. Marcinkiewicz Alan Wang Yi-Lin Chen Jungsoon Lee Zhuyun Liu Xiuli Yang Ulrich Strych Dagnija Tupina Inara Akopjana Maria-Elena Bottazzi Utpal Pal Ching-Lin Hsieh Wen-Hsiang Chen Yi-Pin Lin |
| author_facet | Kalvis Brangulis Jill Malfetano Ashley L. Marcinkiewicz Alan Wang Yi-Lin Chen Jungsoon Lee Zhuyun Liu Xiuli Yang Ulrich Strych Dagnija Tupina Inara Akopjana Maria-Elena Bottazzi Utpal Pal Ching-Lin Hsieh Wen-Hsiang Chen Yi-Pin Lin |
| author_sort | Kalvis Brangulis |
| collection | DOAJ |
| description | Abstract Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YAI183Y and CspZ-YAC187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized female mice. Structural comparison of CspZ-YA with CspZ-YAI183Y and CspZ-YAC187S shows enhanced interactions of two helices adjacent to the FH-binding sites in the mutants, consistent with their elevated thermostability. In line with these findings, protective CspZ-YA monoclonal antibodies show increased binding to CspZ-YA at a physiological temperature (37 °C). In summary, this proof-of-concept study applies structural vaccinology to enhance intramolecular interactions for the long-term stability of a Bb antigen while maintaining its protective epitopes, thus promoting LD vaccine development. |
| format | Article |
| id | doaj-art-1ba741adabff42d5941b8a4c6a1e0174 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1ba741adabff42d5941b8a4c6a1e01742025-08-20T02:16:06ZengNature PortfolioNature Communications2041-17232025-04-0116111610.1038/s41467-025-58182-xMechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccineKalvis Brangulis0Jill Malfetano1Ashley L. Marcinkiewicz2Alan Wang3Yi-Lin Chen4Jungsoon Lee5Zhuyun Liu6Xiuli Yang7Ulrich Strych8Dagnija Tupina9Inara Akopjana10Maria-Elena Bottazzi11Utpal Pal12Ching-Lin Hsieh13Wen-Hsiang Chen14Yi-Pin Lin15Latvian Biomedical Research and Study CentreDivision of Infectious Diseases, Wadsworth Center, NYSDOHDivision of Infectious Diseases, Wadsworth Center, NYSDOHDivision of Infectious Diseases, Wadsworth Center, NYSDOHDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineDepartment of Veterinary Medicine, Virginia-Maryland Regional College of Veterinary Medicine, University of MarylandDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineLatvian Biomedical Research and Study CentreLatvian Biomedical Research and Study CentreDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineDepartment of Veterinary Medicine, Virginia-Maryland Regional College of Veterinary Medicine, University of MarylandDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Pediatrics, National School of Tropical Medicine, Baylor College of MedicineDivision of Infectious Diseases, Wadsworth Center, NYSDOHAbstract Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YAI183Y and CspZ-YAC187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized female mice. Structural comparison of CspZ-YA with CspZ-YAI183Y and CspZ-YAC187S shows enhanced interactions of two helices adjacent to the FH-binding sites in the mutants, consistent with their elevated thermostability. In line with these findings, protective CspZ-YA monoclonal antibodies show increased binding to CspZ-YA at a physiological temperature (37 °C). In summary, this proof-of-concept study applies structural vaccinology to enhance intramolecular interactions for the long-term stability of a Bb antigen while maintaining its protective epitopes, thus promoting LD vaccine development.https://doi.org/10.1038/s41467-025-58182-x |
| spellingShingle | Kalvis Brangulis Jill Malfetano Ashley L. Marcinkiewicz Alan Wang Yi-Lin Chen Jungsoon Lee Zhuyun Liu Xiuli Yang Ulrich Strych Dagnija Tupina Inara Akopjana Maria-Elena Bottazzi Utpal Pal Ching-Lin Hsieh Wen-Hsiang Chen Yi-Pin Lin Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine Nature Communications |
| title | Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine |
| title_full | Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine |
| title_fullStr | Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine |
| title_full_unstemmed | Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine |
| title_short | Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine |
| title_sort | mechanistic insights into the structure based design of a cspz targeting lyme disease vaccine |
| url | https://doi.org/10.1038/s41467-025-58182-x |
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