Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine

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-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> 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-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> 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.

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Publication Details

Journal
Nature Communications
Published
2025-04-06
DOI
https://doi.org/10.1038/s41467-025-58182-x
Citations
4
Primary Topic
Vector-borne infectious diseases
Type
article
Field-Weighted Citation Impact
8.19

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article

Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine

Yi‐Pin Lin, Ināra Akopjana, María Elena Bottazzi, Ching‐Lin Hsieh et al.
4 citations
Nature Communications
Vector-borne infectious diseases
8.19
article

Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine

Yi‐Pin Lin, Ināra Akopjana, María Elena Bottazzi, Ching‐Lin Hsieh, Dagnija Tupiņa, Kalvis Brangulis, Utpal Pal, A. C. Wang, Ashley L. Marcinkiewicz, Wen‐Hsiang Chen, Ulrich Strych, Yilin Chen, Zhuyun Liu, Xiuli Yang, Jill Malfetano, Jungsoon Lee
article en
4 citations

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-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> 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-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> 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.

Nature CommunicationsVol. 16(1)
Tufts University (US), New York State Department of Health (US), Wadsworth Center (US), Latvian Biomedical Research and Study Centre (LV), Baylor University (US), Pomona College (US), Baylor College of Medicine (US), University at Albany, State University of New York (US), Virginia–Maryland College of Veterinary Medicine (US), Riga Stradiņš University (LV), Texas Children's Hospital (US), University of Maryland, College Park (US), The University of Texas at Austin (US)
U.S. Department of Defense, Diamond Light Source, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Congressionally Directed Medical Research Programs
Good health and well-being
Openalex Percentile: Top 2%
Vector-borne infectious diseases
8.19
DOIOpen Access PDFOpenAlex
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