Abstract
Background: Surgery to correct trichiasis is a key component of the World Health Organisation trachoma control strategy, however unfavourable outcomes such as eyelid contour abnormalities (ECA) following surgery are relatively common. This study aimed to understand the transcriptional changes associated with the early development of ECA and the impact of doxycycline, which has anti-inflammatory and anti-fibrotic properties, upon these transcription patterns. Methods: One thousand Ethiopians undergoing trichiasis surgery were enrolled in a randomised controlled trial following informed consent. Equal groups of randomly assigned individuals were orally administered with 100mg/day of doxycycline (n=499) or placebo (n=501) for 28 days. Conjunctival swabs were collected immediately prior to surgery and at one- and six-months post-surgery. 3’ mRNA sequencing was performed on paired baseline and one-month samples from 48 individuals; 12 in each treatment/ECA outcome group. qPCR validation was then performed for 46 genes of interest in 145 individuals who developed ECA at one month and 145 matched controls, using samples from baseline, one and six months. Results: All treatment/outcome groups upregulated genes associated with wound healing pathways at one month relative to baseline, however no individual differences were detected between groups. The summed expression of a highly coexpressed cluster of pro-fibrotic genes was higher in patients that developed ECA in the placebo group relative to controls. qPCR validation revealed that all genes in this cluster and a number of other pro-inflammatory genes were strongly associated with ECA, however these associations were not modulated by trial arm. Conclusions: The development of post-operative ECA is associated with overexpression of pro-inflammatory and pro-fibrotic genes including growth factors, matrix metalloproteinases, collagens and extracellular matrix proteins. There was no evidence that doxycycline modulated the association between gene expression and ECA.
Highlights
Trachoma is a neglected tropical disease and the world’s leading infectious cause of blindness
Trachomatous inflammation and scarring can progress in the absence of detectable chlamydial infection[1,3], it is expected that trichiasis surveillance and management provisions will be required for many years in formerly endemic districts
Here we present evidence that a number of pro-fibrotic and pro-inflammatory genes were upregulated in the conjunctivae of patients who developed eyelid contour abnormalities (ECA) following trichiasis surgery
Summary
Trachoma is a neglected tropical disease and the world’s leading infectious cause of blindness. Disease is initiated during childhood by repeated infection of the conjunctival epithelium with the intracellular bacterium Chlamydia trachomatis. This can lead to recurrent episodes of pathological inflammation which persist throughout the lives of some individuals and are a major risk factor for the development of scarring[1]. 3’ mRNA sequencing was performed on paired baseline and one-month samples from 48 individuals; 12 in each treatment/ECA outcome group. QPCR validation was performed for 46 genes of interest in 145 individuals who developed ECA at one month and 145 matched controls, using samples from baseline, one and six months.
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