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<p><i>Borrelia burgdorferi</i> (<i>Bb</i>) 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 <i>Bb</i> 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 <i>Bb</i> antigen while maintaining its protective epitopes, thus promoting LD vaccine development.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月7日

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  • 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

摘要

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.