NIH grant: Define the mechanisms targeting a B. burgdorferi protein CspZ to prevent Lyme disease infection (1R01AI184476-01A1)

retained text

NIH grant 1R01AI184476-01A1: Define the mechanisms targeting a B. burgdorferi protein CspZ to prevent Lyme disease infection
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Yi-Pin  Lin. Award: $862348.
Start: 2026-08-07T00:00:00.
Lyme disease (LD) is the most prevalent vector-borne disease and the major threat to public health, with 476,000
estimated human cases annually in the US. LD is caused by multiple spirochete bacteria species, including B.
burgdorferi (Bb), the most common LD causative agent in North America. Following a tick bite, Bb first
establishes the infection in skin, often leading to a skin lesion. If untreated, the infection can spread via
bloodstream to impact other organs, leading to severe disease. Effective LD prevention strategies are lacking.
Our long-term goal is to better understand the mechanisms of protectivity to develop safe and potent prevention
against Bb. Complement is a powerful component of the innate defense system. It can be triggered via multiple
pathways. That includes the classical pathway, which is induced by the complex of antibody (Ab), antigen, and
complement C1 proteins, and the alternative pathway, which is triggered by the interaction of the complement
C3b protein with the microbial surface. The activation of complement results in phagocytic clearance and direct
Bb lysis. In the absence of pathogens, complement is inhibited by complement inhibitors to avoid host cell
damage. For example, Factor H (FH) specifically inhibits the alternative pathway. Bb exploits this mechanism by
producing an outer surface protein, CspZ, which recruits FH to its surface, thereby inhibiting complement-
mediated killing and facilitating Bb survival and dissemination. This CspZ protein is immunogenic in humans,
making CspZ as an attractive target for vaccines. We have generated CspZ and CspZ-Y207A/Y211A mutant
(CspZ-YA) that is selectively deficient in FH-binding, leading to exposed epitopes on CspZ-YA FH-binding sites.
We found that CspZ-YA but not CspZ vaccination protects mice from Lyme disease infection. We also generated
monoclonal Abs (mAbs) that recognize the FH-binding sites or other sites. We showed that mAbs to FH-binding
sites lead to robust Bb killing in vitro and in vivo, whereas mAbs to other sites do not. This implied that epitopes
around CspZ-YA’s FH-binding site induce protection. These results also raise the potential protective
mechanisms of those Abs by their F(ab’)2 blocking FH-binding in preventing alternative pathway evasion, and/or
their Fc binding to Fc receptor on phagocytes and C1 on Bb surface to confer phagocytosis- and classical
pathway-mediated Bb killing, respectively. We thus hypothesize that the epitopes around FH-binding sites of
CspZ-YA vaccines trigger Ab to clear Bb by F(ab’)2- and Fc-mediated mechanisms. To test this hypothesis, we
will 1) Define the protective mechanisms of CspZ-YA. 2) Identify the protective epitopes of CspZ-YA. 3) Delineate
the impact of protective CspZ Abs in humans. These studies will identify the CspZ epitopes and protective
mechanisms by which immunization with CspZ-YA confers effective protection against LD. This will build the
foundation for further using rational antigen design and formulation to facilitate vaccine development for more
effective prevention of human LD.

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