Pathogenesis of Progressive Scarring Trachoma in Ethiopia and Tanzania and Its Implications for Disease Control: Two Cohort Studies

Abstract

BackgroundTrachoma causes blindness through a conjunctival scarring process initiated by ocular Chlamydia trachomatis infection; however, the rates, drivers and pathophysiological determinants are poorly understood. We investigated progressive scarring and its relationship to conjunctival infection, inflammation and transcript levels of cytokines and fibrogenic factors.Methodology/Principal FindingsWe recruited two cohorts, one each in Ethiopia and Tanzania, of individuals with established trachomatous conjunctival scarring. They were followed six-monthly for two years, with clinical examinations and conjunctival swab sample collection. Progressive scarring cases were identified by comparing baseline and two-year photographs, and compared to individuals without progression. Samples were tested for C. trachomatis by PCR and transcript levels of S100A7, IL1B, IL13, IL17A, CXCL5, CTGF, SPARCL1, CEACAM5, MMP7, MMP9 and CD83 were estimated by quantitative RT-PCR. Progressive scarring was found in 135/585 (23.1%) of Ethiopian participants and 173/577 (30.0%) of Tanzanian participants. There was a strong relationship between progressive scarring and increasing inflammatory episodes (Ethiopia: OR 5.93, 95%CI 3.31–10.6, p<0.0001. Tanzania: OR 5.76, 95%CI 2.60–12.7, p<0.0001). No episodes of C. trachomatis infection were detected in the Ethiopian cohort and only 5 episodes in the Tanzanian cohort. Clinical inflammation, but not scarring progression, was associated with increased expression of S100A7, IL1B, IL17A, CXCL5, CTGF, CEACAM5, MMP7, CD83 and reduced SPARCL1.Conclusions/SignificanceScarring progressed in the absence of detectable C. trachomatis, which raises uncertainty about the primary drivers of late-stage trachoma. Chronic conjunctival inflammation appears to be central and is associated with enriched expression of pro-inflammatory factors and altered expression of extracellular matrix regulators. Host determinants of scarring progression appear more complex and subtle than the features of inflammation. Overall this indicates a potential role for anti-inflammatory interventions to interrupt progression and the need for trichiasis disease surveillance and surgery long after chlamydial infection has been controlled at community level.

Risk factors for incidence of trachomatous scarring in a cohort of women in low endemic district

“…Two parallel prospective cohort studies in 2008 and 2009 that looked at progression of scarring found an association with episodes of clinical inflammation. This inflammation was also associated with factors of innate immune origin 24. Interestingly, progression, unlike incidence, did not show an association with C. trachomatis , gender or age 11.…”

Immunopathogenesis of Chlamydial Infections

“…A similar process could be envisioned for ongoing stimulation or targeting of pathogenic T cell responses to sites of sequelae well after clearance of the infection. Support for this line of thought also comes from a recent trachoma study where scarring and clinical inflammation continued to progress in the absence of detectable infection over a 2-year period, and there was an association with clinical inflammation, not scarring progression, of multiple innate immune markers such as S100A7, IL1B, IL17A, CXCL5, CTGF, CEACAM5, MMP7, CD83, and reduced SPARCL1 (Burton et al 2015). These results support the possibility of a Chlamydia -specific adaptive immune response in chlamydial pathogenesis.…”

The ocular surface, coronaviruses and COVID‐19

“…30 Table 1 presents a comparison of receptors for SARS-CoV-2, SARS-CoV and MERS-CoV on ocular surface and lung cells. [31][32][33][34][35][36][37][38][39] Expression of the gene for ACE2 has been shown in corneal and conjunctival epithelial cells, and preliminary evidence has been presented for the presence of the protein associated with these cells. 40 The isolated surface protein S240 of SARS-CoV can bind to conjunctival epithelial and fibroblast cells and corneal epithelial cells, with this binding inhibited by soluble ACE2, indicating that the binding was being mediated through cell-surface ACE2.…”

“…37 The only report of CD66e in the conjunctiva was from patients with trachoma who had gene expression in their upper palpebral conjunctiva. 39 There are no reports of CD26 or CD66e in cornea or tears. CD13 has not been reported on conjunctival or corneal epithelial cells, but has been found on human corneal keratocytes.…”

“…Co-receptor +/− (palpebral conjunctiva) 39 + (bronchial and alveolar epithelium) 32 +: the receptor has been found, −: there are no reports of the receptor on the ocular surface, +/−: found in tissue but only on non-virally-mediated inflamed tissue. , that viral particles on the eye can travel to the lung but that they are either reduced in their virulence or the numbers that reach the lung are very low, and so the resulting infection was very mild.…”