Language
English
Publication Date
4-7-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-58182-x
PMID
40189575
PMCID
PMC11973211
PubMedCentral® Posted Date
4-7-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Borrelia burgdorferi, Lyme Disease, Animals, Female, Mice, Lyme Disease Vaccines, Bacterial Proteins, Humans, Antigens, Bacterial, Antibodies, Bacterial, Crystallography, X-Ray, Complement Factor H, Antibodies, Monoclonal, Models, Molecular, Nanocrystallography, Immunization, Protein design, Protein vaccines
Published Open-Access
yes
Recommended Citation
Brangulis, Kalvis; Malfetano, Jill; Marcinkiewicz, Ashley L; et al., "Mechanistic Insights Into the Structure-Based Design of a CspZ-Targeting Lyme Disease Vaccine" (2025). Faculty and Staff Publications. 5862.
https://digitalcommons.library.tmc.edu/baylor_docs/5862