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Title: The characterisation of natural antimicrobial peptides in the female reproductive tract
Author: Fleming, Diana Claire
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Changes in lifestyle and contraceptive practices have favoured the spread of sexually transmitted infections. The female reproductive tract is thus increasingly exposed to potential pathogens. Mucosal epithelial surfaces provide a first line of defence against the entry of these pathogens. The innate immune response is fundamental to the initial recognition of pathogens and influences the subsequent cascade of effector mechanisms. The natural antimicrobial peptides are a recently described innate immune defence mechanism, which in common with other mucosal surfaces, have been identified within the female reproductive tract. The aims of this thesis are (1) To characterise the natural antimicrobials, human β defensin 1 and 2 (HBD1 and HBD2), secretory leukocyte protease inhibitor (SLPI) and granulysin, within the human endometrium through the menstrual cycle and in early pregnancy in vivo. (2) To assess the effect of exogenous sex steroids and chlamydial infection on this expression. (3) To investigate the expression and regulation of the natural antimicrobial peptides and pattern recognition receptors in vitro. (4) To examine some of the early immune responses to Chlamydia trachomatis infection in vitro. All the natural antimicrobials showed cyclical variation. HBD1 was maximal in the mid secretory phase, granulysin in the late secretory phase, HBD2 in the menstrual phase and SLPI in the late secretory and menstrual phases. SLPI, HBD1 and granulysisn were present in first trimester decidua, while levels of HBD2 were undetectable. Exogenous sex steroid, administered as the combined oral contraceptive pill and the levonorgestrel releasing intrauterine system (LNG-IUS) significantly decreased mRNA expression of HBD1 and 2 and granulysin. There was no significant effect of chlamydial infection on natural antimicrobial mRNA expression in first trimester decidual samples. Natural antimicrobials may play a role in the acquisition of infection and this is an important consideration in future contraceptive development and in the outcome of pregnancy. Mimics of infection such as lipopolysaccharide (LPS - a mimic of Gram negative infection) and polyinosinic-polycytidylic acid (a mimic of viral infection) altered the mRNA expression of the natural antimicrobials in primary endometrial epithelial cells in vitro. mRNA expression of HBD1 was increased while SLPI mRNA expression was decreased. These mimics of infection are recognised by pathogen recognition receptors, which include the Toll-like receptor (TLR) family. Variable modulation of TLR 4 and the co-receptor CD 14 were observed following treatment with LPS. Infection of the cervical epithelial cell line (HeLa) with Chlamydia trachomatis in vitro resulted in the up-regulation of SLPI, TLR9 and inflammatory cytokines such as IL-8 and IL-1. These data suggest that epithelial cells and the resulting cascade of innate immune responses play a central role in the events following pathogen invasion of the female reproductive tract. This work furthers our understanding of the modulation of the natural antimicrobials, which act as an initial innate immunological barrier to infection. As a result of this work, further research might aim to manipulate these substances, or the effector mechanisms that lead to their expression. It may thus be possible to prevent or treat sexually transmitted infections and subsequently impact on the consequences of these infections such as infertility and adverse pregnancy outcomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available