Elucidating the chlamydial growth characteristics, infection factors, and host responses to persistent chlamydial infection in women

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๐˜Š๐˜ฉ๐˜ญ๐˜ข๐˜ฎ๐˜บ๐˜ฅ๐˜ช๐˜ข ๐˜ต๐˜ณ๐˜ข๐˜ค๐˜ฉ๐˜ฐ๐˜ฎ๐˜ข๐˜ต๐˜ช๐˜ด is an obligate intracellular parasite and the leading cause of sexually transmitted bacterial infections in the human urogenital tract. Clinical manifestations of chlamydial infection include urethritis, cervicitis, pelvic inflammatory disease and tubal factor infertility. These pathological conditions are caused by the immune response to both acute and chronic chlamydial infections. Evidence suggests a high proportion of infections remain subclinical until spontaneous resolution or the commencement of symptoms leads to a diagnosis. Therefore, a substantial proportion of the morbidity and burden associated with chlamydia can likely be attributed to unresolved and untreated infections. While treatment with azithromycin is highly effective, treatment failure does occur. The mechanisms of treatment failure and its effects on fertility are poorly understood. Unlike other bacterial pathogens, ๐˜Š. ๐˜ต๐˜ณ๐˜ข๐˜ค๐˜ฉ๐˜ฐ๐˜ฎ๐˜ข๐˜ต๐˜ช๐˜ด lacks stable genotypic resistance to macrolides. Another key difference between ๐˜Š๐˜ฉ๐˜ญ๐˜ข๐˜ฎ๐˜บ๐˜ฅ๐˜ช๐˜ข and many other bacteria is the constant interaction with its host cell. Thus, it was hypothesised that the unique intracellular niche and developmental cycle of ๐˜Š. ๐˜ต๐˜ณ๐˜ข๐˜ค๐˜ฉ๐˜ฐ๐˜ฎ๐˜ข๐˜ต๐˜ช๐˜ด are important microbial factors which could affect treatment efficacy. To test this, several host and chlamydial factors were investigated. 16S rRNA gene amplicon sequencing of vaginal and cervical swabs and endometrial biopsies from participants of a case-control fertility study revealed that similarities in the microbial populations of the vagina and cervix were not predictive of those in the endometrium. While there was no association between microbial community compositions and fertility status identified, ๐˜œ๐˜ณ๐˜ฆ๐˜ข๐˜ฑ๐˜ญ๐˜ข๐˜ด๐˜ฎ๐˜ข spp. were overrepresented amongst infertile women. The endometrial expression of several genes involved in immunity and reproductive function showed no association with microbial community composition, however, the gene which encodes tenascin-C was over-expressed in women who had a self-reported history of miscarriage. Comparisons of clinical isolates from women treated for chlamydial infections showed no significant differences in developmental or stress phenotypes but suggested that the subtle differences observed using ๐˜ช๐˜ฏ ๐˜ท๐˜ช๐˜ต๐˜ณ๐˜ฐ models may not truly reflect the complexity of ๐˜ช๐˜ฏ ๐˜ท๐˜ช๐˜ท๐˜ฐ infectious processes. Finally, analysis of host and chlamydial gene expression before and after antibiotic treatment showed no association with outcome but yielded valuable information about the host and pathogen during the period following treatment. In particular, chlamydial gene expression was upregulated after they had survived treatment with azithromycin. This project has contributed towards current knowledge and increases the fieldโ€™s understanding of the host and chlamydial factors involved in treatment failure and infertility. Additionally, it provides insight for future investigations of these important and complex interactions between humans and the bacteria which have evolved alongside us.
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