Microbial, immunological and biochemical factors associated with Chlamydia trachomatis urogenital infections in women

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Microbial, immunological and biochemical factors associated with Chlamydia trachomatis urogenital infections in women

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Title: Microbial, immunological and biochemical factors associated with Chlamydia trachomatis urogenital infections in women
Author/Creator: Ziklo, Noa
Supervisor: Timms, Peter
Description: Sexually transmitted Chlamydia trachomatis infections continue to be a widespread health concern. Despite all efforts, the natural course of C. trachomatis infections is still not fully understood, nor is the precise immune profile that is associated with protection. Protective immunity against C. trachomatis is characterized by interferon-gamma (IFN-γ)-mediated, intracellular tryptophan depletion, due to upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO1). IDO1 catabolizes the amino acid tryptophan into kynurenine, subsequently inhibiting the tryptophan auxotroph Chlamydia. One hypothesis in the field suggests that indole-producing bacteria in the vaginal microbiota might provide an alternative source for tryptophan, and therefore may influence the infection course. To investigate this hypothesis, we first used an in vitro model to rescue C. trachomatis from tryptophan depletion using supernatant from indole-positive versus indole-negative strains of the vaginal microorganism, Prevotella. Furthermore, we analyzed vaginal secretion samples to determine the range of physiological indole concentrations, and their potential in rescuing tryptophan-starved Chlamydia. We found that only supernatants from the indole-positive strains, P. intermedia and P. nigrescens, were able to rescue tryptophan-starved C. trachomatis. In spite of the complexity of vaginal secretions, we also demonstrated that for some vaginal specimens with higher indole levels, there was a link to higher recovery of the Chlamydia under tryptophan-starved conditions. Subsequently, we utilized a cohort of women who were either, Chlamydia negative, Chlamydia positive with a single infection, or Chlamydia positive with repeated infection. We characterized their vaginal microbiota composition, cytokine response, tryptophan, kynurenine and indole concentrations directly in vaginal secretions. We found that women with repeated C. trachomatis infection had significantly higher kynurenine/tryptophan ratios, as well as significantly elevated kynurenine levels. Moreover, low vaginal tryptophan levels were significantly associated with microbiota of community state type (CST) IV. Additionally, we were able to evaluate the indole-producing bacterial proportion in the vaginal microbiota of women in our cohort, and found a trend of higher vaginal indole/tryptophan ratios in women with Chlamydia infections. Further examination of mRNA levels of key genes in this pathway revealed an association between higher kynurenine and IDO1 levels in repeatedly infected women, leading to a local regulatory immunity demonstrated by high expression levels of FoxP3 and TGF-β following antibiotic treatment for Chlamydia.
Description: Submitted in the fulfilment of the requirements of the degree of Doctor of Philosophy, University of the Sunshine Coast, 2017.
Year: 2017
Subject: FoR 0605 (Microbiology) | FoR 1107 (Immunology) | tryptophan | kynurenine | indole | vaginal microbiota | interferon-gamma | Chlamydia trachomatis | immune response

Collection(s): University of the Sunshine Coast Theses
Resource Type: Thesis (PhD)

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