Defining Chlamydia trachomatis adhesion factor epitope-specific antibody responses, functionality, and roles in protection against urogenital infection - PROJECT SUMMARY
Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection worldwide and causes
serious medical complications in women, including pelvic inflammatory disease, ectopic pregnancy, and
infertility. Therefore, a vaccine is urgently needed. One obstacle to successful vaccine development is a lack of
a comprehensive understanding of the protective immune response to Ct infection, including the role of
epitope-specific antibodies. The overall objective of this fellowship proposal is to finely map the antibody
response in women with an acute history of Ct infection, determine immunodominant epitopes of Ct antigens,
investigate differential antibody responses between women with a positive Ct infection outcome (defined as no
Ct reinfection at 3-months follow-up or spontaneous resolution of Ct infection without antibiotic treatment) and
women who experience Ct reinfection, and determine the functionality and protective capacity of these
antibody responses. The central hypothesis to be tested is that antibody responses will differ between patients
who had a positive Ct infection outcome than those who experienced a reinfection of Ct and that these epitope-
specific antibodies to adhesion factors of Ct will play an important role in protection (binding to Ct-infected
cells, neutralization, antibody-mediated neutrophil killing, and protection from a Ct challenge in murine models).
The long-term goal is to inform vaccine design through better understanding of protective immune responses,
culminating in an effective Ct vaccine. The following specific aims will be used to test the hypothesis:
Specific Aim 1: Define the natural serum antibody response to urogenital Ct infection in women. Utilizing Deep
Sequence-Coupled Biopanning, a novel technology that uses a small amount of human sera to finely map the
antibody response at an epitope-level, I will elucidate the natural antibody response to Ct infection. This will
empirically determine immunodominant epitopes and B cell epitopes to 24 Ct antigens. I will also define
differential antibody responses between women who experienced a positive Ct infection outcome compared to
those who experienced a Ct reinfection within 3-months of antibiotic treatment.
Specific Aim 2: Investigate Ct adhesion factor epitope-specific antibody functions. Antibodies to
immunodominant epitopes and differential antibody response between patient cohorts (SA1) will be tested for
functionality to determine protective capacity against Ct infection. Using in vitro techniques, I will determine if
these epitope-specific antibodies can bind to Ct, have neutralizing capacity, and can function in antibody-
mediated neutrophil Ct killing. I will also determine if these antibodies can protect against a Ct infection in a
murine model by monitoring Ct infection, bacterial shedding, Ct clearance, and upper genital tract pathology.
Together, this proposal will investigate the specificity, functionality, and role of epitope-specific antibodies in
protection against Ct infection and has the potential to significantly advance the Ct field by understanding
protective immune responses and informing future vaccine design.
