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Title: Identification of Chlamydia trachomatis immune targets through immunological and population-genomic screens and elucidation of potential roles in bacterial pathogenesis
Author: Pickering, H.
ISNI:       0000 0004 6349 6859
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2017
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Ocular infection by Chlamydia trachomatis (Ct) results in trachoma, the leading infectious cause of blindness. Infection clears naturally, but repeated exposure in endemic areas and resulting inflammation promote tissue damage leading eventually to blinding sequelae. Antibiotic treatment as part of community-based intervention reduces prevalence of infection and disease but rarely eliminates the problem completely and progression to scarring and blindness does still occur. Sixty years of vaccine trials have produced variable results therefore new candidate antigens and better understanding of the underlying causes of infection and disease are required. Serum samples from trachoma-endemic communities in The Gambia were tested against the arrayed Ct proteome to identify antibody responses associated with protection from infection and from scarring disease. More focussed global antibody profiles were associated with partial immunity to infection. Several antibody targets were identified as individually associated with infection and disease outcome. Clinical Ct isolates collected from Guinea-Bissau were screened for evidence of natural selection to identify further immune targets and to validate those discovered through serological techniques. Evidence of positive selection was found for known Ct virulence factors, there was little evidence of balancing selection. Antibody targets associated with susceptibility to infection and scarring had evidence of purifying selection. One of the Ct antigens, CT442, identified as being an immune target and under natural selection was characterised further using cell-culture models. It was localised to the inclusion membrane through immunofluorescence microscopy, the primary point of contact with the host, and potentially interacted with pathways involved in intracellular vesicular trafficking based on interacting proteins identified through mass spectrometry. Ct infection is shown to stimulate a broad, polyclonal antibody response, individuals with more focussed responses are better protected from persistent infection and scarring progression. Purifying selection in antibody targets which associate with poor resolution of infection suggests two possible hypotheses for Ct evasion of immune responses. The decoy hypothesis, in which Ct actively promotes immune responses against irrelevant, decoy antigens to divert antibody responses away from protective antigens, and the blocking hypothesis, in which antibodies against certain Ct surface antigens block the binding of neutralising antibodies. Evidence of selection in CT442 show it is important but unlikely essential for Ct survival, the functions that are driving this evolution require further study.
Supervisor: Holland, M. J. ; Hayward, R. Sponsor: Bloomsbury Colleges
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral