Thesis defense Lobna Medfai

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Chlamydia trachomatis (C. trachomatis), an obligate intracellular bacterium, is the leading cause of sexually transmitted bacterial infections globally, impacting both the ocular epithelium and the genital tract. Despite its prevalence, the absence of a vaccine against C. trachomatis stems from the intricate nature of its life cycle and its complex interaction with the host. C. trachomatis adeptly manipulates the host trafficking network to establish its own protective replication niche, termed the inclusion, within host cells, effectively evading host defenses, including vesicular compartments. However, occasional "leakages" during infection expose the bacterium or its antigens in the host cell cytoplasm, facilitating antigen processing and presentation. As an obligate intracellular pathogen, CD8+ T cell responses are expected to play a crucial role during infection and following vaccination for the induction of long-lasting memory and protection against repeated infections, especially with the increasing amount of evidence about the role of CD8+ T cells during chlamydia infection. The role and importance of CD8+ T cells are discussed in detail in the introduction of this thesis.

Furthermore, the experimental work in this thesis aims to enhance cellular responses following immunization, specifically CD8+ T cell responses. On the one hand, we examined the immunopeptidome of chlamydia-infected cells in an attempt to better understand the mechanisms underlying host-pathogen interaction during chlamydia infection and to identify potential immunogenic targets for vaccine formulation to enhance CD8+ T cell response. Immunopeptidome analysis at two different time points of the C. trachomatis infection cycle revealed new and surprising findings about the characteristics of presented peptides on MHC I molecules and their cognate proteins, enlarging the spectrum of features and criteria needed for the selection of good antigen candidates.

On the other hand, we explore different innovative vaccination platforms in various chapters of this thesis to improve cellular responses, namely nucleic acid vaccines, outer membrane vesicles, and particulate bodies. All the platforms use a model antigen, CTH522, a recombinant protein derived from the major outer membrane protein of different chlamydia serovars. Each of the platforms showed encouraging results and allowed us to identify new immunogenic epitopes that elicited significant CD8 and CD4 T cell responses. In addition to their immunogenicity profile, the bacterial-based vaccines were the most efficient in providing protection against challenge experiments.

The work done in this thesis is a step further in understanding the intricate interaction between C. trachomatis and its host and paves the way for promising immunization strategies that enhance cellular responses. Building on the findings of this thesis would help improve vaccine formulation and achieve wider protection against different C. trachomatis serovars.