What happens after trachoma infection to transform cells into scar tissue?
- Type of funding: PhD Studentship
- Grant Holder: Dr Martin Holland
- Institute: London School of Hygiene and Tropical Medicine
- Region: London
- Start date: October 2012
- End Date: September 2015
- Eye Category:
Trachoma is the world’s leading cause of blindness due to infection. Repeated infection in the lining of the eyelid (the conjunctiva) with bacteria called Chalamydia trachomatis leads to long-term inflammation. It also makes the tissue prone to tightening and scarring. The immediate infection can be treated with antibiotics but the process of scarring can last for many years afterwards. As it does, the tight tissue pulls the eyelids inwards and the eyelashes scratch the cornea. Eventually the cornea (the front surface of the eye which is usually clear) becomes cloudy and light can’t get through.
The way that cells in the conjunctiva’s outer layer respond to the infection is key to the scarring that happens in trachoma. Inflammation triggers a process that transforms them into cells that can become scar tissue, but we don’t understand enough about how that happens.
In this project the research team is studying how these cells behave in a lab dish in response to C. trachomatis infection. In particular they will be trying to find out whether the infection triggers any long-term changes to the cell that could switch its genes on or off without changing the gene itself (known as epigenetic changes). If so, it could explain why trachoma can continue long after the infection has gone.
They will also test samples from patients to see whether their findings from the lab dish match what happens in people. The results will give us a better understanding of trachoma and could open up new avenues for developing treatment.
Induction of Type 2 Epithelial-Mesenchymal Transitions as a result of Chlamydia trachomatis driven inflammation and its role in trachoma
Trachoma is the leading infectious cause of blindness worldwide. Repeated conjunctival infection with Chlamydia trachomatis results in chronic inflammation and a pro-fibrotic environment. Whilst acute infection can be treated with antibiotics, pro-fibrotic responses to infection appear to persist for many years: conjunctival scarring progresses, causing in-turning eyelids (entropion) / eyelashes (trichiasis) and blinding corneal opacification. The conjunctival epithelial cell response to C. trachomatis is central to this inflammatory-scarring process. The cellular and molecular pathways involved in inflammation are well characterised, but the mechanisms by which host epithelial cells contribute to fibrosis are less clear. During repair of the epithelial barrier or as direct response to the cytokine milieu, epithelial cells are induced to transform to mesenchymal or fibroblast like cells in a process known as epithelial-mesenchymal transition (EMT).
The team are establishing an in vitro model of conjunctival EMT with the aim of describing the host-pathogen factors that drive and maintain it. They are examining epigenetic changes associated with EMT, resulting from inflammation. The stable nature of epigenetic change implies that the initial inducers of repression and modification need only be transiently expressed and offers an explanation as to why disease can continue to progress without infection. Further studies of conjunctival biopsies and surface swabs will be used to test whether results found in vitro translate into clinical differences and are indicative of population responses. This study will provide much needed information on molecular mechanisms underlying the pathogenesis of scarring trachoma and will allow the team to identify and test new targets for therapeutic intervention.
The team has discovered a number of small molecules – known as ‘microRNAs’ – that are affected during different stages of trachoma. MicroRNAs control the activity of many other genes, for example by switching them on or off.
In the initial stage of trachoma when both infection and inflammation are present, the microRNA known as miR-155 increases and another, miR-184, is decreases as inflammation gets worse. And two other microRNAs they’ve found (miR-147b and miR-1285) are increased in adults with scarring and inflammatory trachoma.
The team has also found that eyelid tissue from people with scarring trachomacontains more pro-inflammatory signalling molecules IL-1ß and S1007 than healthy tissue, and they have identified connective tssue growth factor as a potential target for treatment.
- Derrick T, Luthert PJ, Jama H, Hu VH, Massae P, Essex D, et al. Increased Epithelial Expression of CTGF and S100A7 with Elevated Subepithelial Expression of IL-1β in Trachomatous Trichiasis. PLOS Negl Trop Dis. 2016 Jun 1;10(6):e0004752.
Derrick T, Last AR, Burr SE, Roberts C h., Nabicassa M, Cassama E, et al. Inverse relationship between microRNA-155 and -184 expression with increasing conjunctival inflammation during ocular Chlamydia trachomatis infection. BMC Infectious Diseases. 2016;16:60.
- Derrick T, Roberts C h, Rajasekhar M, Burr SE, Joof H, Makalo P, et al. Conjunctival MicroRNA expression in inflammatory trachomatous scarring. PLoS Negl Trop Dis. 2013;7(3):e2117.