Identification of responses to CAP1 peptides in trachomatous subjects

Lead Research Organisation: MRC Unit, The Gambia

Abstract

This work demonstrated the usefulness of studying host conjunctival gene expression. Multiple cytokines and genes involved in the immune response were investigated over time in same individuals. This identified discrete responses that segregated with infection and disease. It challenges current ideas about the mechanisms of control of ocular chlamydial infection which are largely built around laboratory isolates and in vitro cell lines. Because it was possible for the first time to make quantitative measures of bacterial load and natural defence mechanisms which control chlamydial replication in vitro. The findings therefore contribute to overall science base required for the proposed development of a new vaccine. These basic mechanisms also likely underlie disease caused by chlamydiae in the genital tract. Since chlamydial genital tract infection is the most prevalent STI and a major cause of infertility in women the results found here should have wider clinical relevance.

Technical Summary

The overall aim is to identify an correlate of immunity or disease to naturally acquired ocular infection or disease caused by Chlamydia trachomatis. This important since WHO estimates that at least 600 million people are at risk of infection of which approximately 6 million are blind as a consequence. Immunity to trachoma is still not clearly understood and there is no licensed vaccine or vaccine trail since the 1960s. The objective is to define the immune response at the conjunctival surface (site of infection) during episodes of disease and infection. Ocular chlamydial disease is clinically diagnosed by the appearance of characteristic inflammatory changes and development of lymphoid follicles in the conjunctiva. Nucleic acid amplification tests and relatively non-invasive methods of sampling the conjunctival surface (by swabbing) can be used to quantify the expression of chlamydial and host genes. Using quantitative real-time PCR to detect the presence of C. trachomatis (CT) 16S rRNA and human IL-1?, IL-10, IL-12p40, IFN-? and TNF-? transcripts the immune response at the conjunctival surface was examined in a cohort of children living in a trachoma-endemic village in The Gambia. Elevated cytokine transcript levels were associated with the presence of CT 16S rRNA. Sub-clinical infection (CT infection without clinical signs of disease) elicited an immune response that is pro-inflammatory in nature, with elevations in the transcription of IL-1?, IFN-? and IL-12p40. Clinically apparent infections were associated with the elevation of mRNA for the multifunctional cytokine TNF-? (fibrotic, type 1 inflammatory and regulatory) and the counter regulatory cytokine, IL-10, in addition to the other pro-inflammatory cytokines. A positive correlation between IFN-? transcript levels and the amount of CT 16S rRNA expressed in conjunctiva was found.

Publications

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Alexander ND (2005) An index of community ocular Chlamydia trachomatis load for control of trachoma. in Transactions of the Royal Society of Tropical Medicine and Hygiene

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Andreasen AA (2008) Chlamydia trachomatis ompA variants in trachoma: what do they tell us? in PLoS neglected tropical diseases

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Burton MJ (2005) Long term outcome of trichiasis surgery in the Gambia. in The British journal of ophthalmology

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Burton MJ (2007) Bacterial infection and trachoma in the gambia: a case control study. in Investigative ophthalmology & visual science

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Burton MJ (2006) Conjunctival chlamydial 16S ribosomal RNA expression in trachoma: is chlamydial metabolic activity required for disease to develop? in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America