Immunofibrogenic Gene Expression Patterns in Tanzanian Children with Ocular Chlamydia trachomatis Infection, Active Trachoma and Scarring: Baseline Results of a 4-Year Longitudinal Study

Abstract

Trachoma, caused by Chlamydia trachomatis, is the world's leading infectious cause of blindness and remains a significant public health problem. Much of trachomatous disease pathology is thought to be caused indirectly by host cellular and immune responses, however the immune response during active trachoma and how this initiates progressive scarring is not clearly understood. Defining protective vs. pathogenic immune response to C. trachomatis is important for vaccine design and evaluation. This study reports the baseline results of a longitudinal cohort of Tanzanian children, who were monitored for 4 years in order to determine the immunofibrogenic and infectious correlates of progressive scarring trachoma. In this cohort baseline, 506 children aged 6–10 years were assessed for clinical signs, infection status and the expression of 91 genes of interest prior to mass azithromycin administration for trachoma control. C. trachomatis was detected using droplet digital PCR and gene expression was measured using quantitative real-time PCR. The prevalence of follicles, papillary inflammation and scarring were 33.6, 31.6, and 28.5%, respectively. C. trachomatis was detected in 78/506 (15.4%) individuals, 62/78 of whom also had follicles. C. trachomatis infection was associated with a strong upregulation of IFNG and IL22, the enrichment of Th1 and NK cell pathways and Th17 cell-associated cytokines. In individuals with inflammation in the absence of infection the IFNG/IL22 and NK cell response was reduced, however, pro-inflammatory, growth and matrix factors remained upregulated and mucins were downregulated. Our data suggest that, strong IFNG/IL22 responses, probably related to Th1 and NK cell involvement, is important for clearance of C. trachomatis and that the residual pro-inflammatory and pro-fibrotic phenotype that persists after infection might contribute to pathological scarring. Interestingly, females appear more susceptible to developing papillary inflammation and scarring than males, even at this young age, despite comparable levels of C. trachomatis infection. Females also had increased expression of a number of IFNγ pathway related genes relative to males, suggesting that overexpression of this pathway in response to infection might contribute to more severe scarring. Longitudinal investigation of these factors will reveal their relative contributions to protection from C. trachomatis infection and development of scarring complications.

DjinniChip: Evaluation of a novel molecular rapid diagnostic device for the detection of Chlamydia trachomatis in trachoma-endemic areas

“…In February 2012, we recruited a cohort of children from three adjacent trachoma endemic villages in Kilimanjaro and Arusha regions, Northern Tanzania. All children, between the ages 3 and 11 years, who were normally resident in one of the three villages, were eligible for inclusion (n =666) [7]. 616 children were enrolled and the cohort was initially followed-up every 3 months for 4 years, for a total of 17 time points.…”

“…Timepoint 14 (August 2015) was selected for this evaluation and 428 children were seen, 9 months after the last mass community treatment with antibiotic as detailed by the SAFE strategy. Conjunctival swabs were collected as previously described using sterile polyester-tipped swabs [7,8]. The rst swab was collected into 250µl RNA later and was used elsewhere [7][8][9], whilst the second swab was collected dry and stored at -80°C until used in this study.…”

“…Conjunctival swabs were collected as previously described using sterile polyester-tipped swabs [7,8]. The rst swab was collected into 250µl RNA later and was used elsewhere [7][8][9], whilst the second swab was collected dry and stored at -80°C until used in this study. 0.5% of swabs collected were 'air' control swabs in order to test for eld and laboratory contamination.…”

Biological approaches for hypertrophic scars

“…In aberrant wound healing, LCs stimulated naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)‐1, a member of the Ig immunoregulatory receptor family, infiltrating hypoxic areas of active HSs, pointing to the pathogenic role in wound repair disorders . Besides, it has been found that there is a correlation of NK cell, T‐cell, and scarring . For example, NK cells inhibit the progression of liver fibrosis through targeting and clearing the hepatic astrocytes directly which secrete ECM, suggesting an important role in antifibrosis .…”

“…186 Besides, it has been found that there is a correlation of NK cell, T-cell, and scarring. 187 For example, NK cells inhibit the progression of liver fibrosis through targeting and clearing the hepatic astrocytes directly which secrete ECM, suggesting an important role in antifibrosis. 188 Also, we mentioned in the previous section that macrophages of different phenotypes play different roles in the scar formation.…”