Multiple Chlamydiaceae species in trachoma: implications for disease pathogenesis and control.
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ABSTRACT:
SUBMITTER: Dean D
PROVIDER: S-EPMC2174965 | biostudies-literature | 2008 Jan
REPOSITORIES: biostudies-literature
Publications
Multiple Chlamydiaceae species in trachoma: implications for disease pathogenesis and control.
Dean Deborah D Kandel Ram P RP Adhikari Him K HK Hessel Tracey T
PLoS medicine 20080101 1
<h4>Background</h4>Chlamydia trachomatis is a unique obligate intracellular bacterium that remains the leading cause of sexually transmitted bacterial diseases and preventable blindness worldwide. Chronic ocular infections are referred to as trachoma, and predominate in developing countries. Since 2001, the World Health Organization has promoted control strategies including antibiotics, improved hygiene, and environmental measures with limited success. Consequently, a vaccine is urgently needed. ...[more]
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Project description:Trachoma is the leading cause of preventable blindness. Commercial assays do not discriminate among all Chlamydiaceae species that might be involved in trachoma. We investigated whether a commercial Micro-ArrayTube could discriminate Chlamydiaceae species in DNA extracted directly from conjunctival samples from 101 trachoma patients in Nepal. To evaluate organism viability, we extracted RNA, reverse transcribed it, and subjected it to quantitative real-time PCR. We found that 71 (70.3%) villagers were infected. ArrayTube sensitivity was 91.7% and specificity was 100% compared with that of real-time PCR. Concordance between genotypes detected by microarray and ompA genotyping was 100%. Species distribution included 54 (76%) single infections with Chlamydia trachomatis, C. psittaci, C. suis, or C. pecorum, and 17 (24%) mixed infections that includied C. pneumoniae. Ocular infections were caused by 5 Chlamydiaceae species. Additional studies of trachoma pathogenesis involving Chlamydiaceae species other than C. trachomatis and their zoonotic origins are needed.
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Project description: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.
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Project description:BackgroundTrachoma is thought to be common over large parts of Southern Sudan. However, many areas of the country, particularly west of the Nile, have not yet been surveyed. The aim of this study was to confirm whether trachoma extends into Western Equatoria State from neighboring Central Equatoria, where trachoma is highly prevalent, and whether intervention with the SAFE strategy is required.Methods and findingsPopulation-based cross-sectional surveys were conducted using a two-stage cluster random sampling method to select the study population. Subjects were examined for trachoma by experienced graders using the World Health Organization (WHO) simplified grading scheme. Two counties thought to be most likely to have trachoma were surveyed, Maridi and Mundri. In Maridi, prevalence of one of the signs of active trachoma (trachomatous inflammation-follicular (TF)) in children aged 1-9 years was 0.4% (95% confidence interval (CI), 0.0%-0.8%), while no children showing the other possible sign, trachomatous inflammation-intense (TI), were identified. No trachomatous trichiasis (TT) was found in those aged under 15, and prevalence was 0.1% (95% CI, 0.0%-0.4%) in those aged 15 years and above. In Mundri, active trachoma was also limited to signs of TF, with a prevalence of 4.1% (95% CI, 1.4%-6.9%) in children aged 1-9 years. Again, no TT was found in those aged under 15, and prevalence in those aged 15 years and above was 0.3% (95% CI, 0.0%-0.8%).ConclusionTrachoma prevalence in the east of Western Equatoria State is below the WHO recommended intervention threshold for mass drug administration of antibiotic treatment in all villages. However, the prevalence of TF and TT in some villages, particularly in Mundri County, is sufficiently high to warrant targeted interventions at the community level. These results demonstrate that trachoma is not a major public health problem throughout Southern Sudan. Further studies will be required to determine trachoma prevalence in other areas, particularly west of the Nile, but there are presently no resources to survey each county. Studies should thus be targeted to areas where collection of new data would be most informative.
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Project description:BackgroundTrachoma, the worldwide leading infectious cause of blindness, is due to repeated conjunctival infection with Chlamydia trachomatis. The effects of control interventions on population levels of infection and active disease can be promptly measured, but the effects on severe ocular sequelae require long-term monitoring. We present an age-structured mathematical model of trachoma transmission and disease to predict the impact of interventions on the prevalence of blinding trachoma.Methodology/principal findingsThe model is based on the concept of multiple reinfections leading to progressive conjunctival scarring, trichiasis, corneal opacity and blindness. It also includes aspects of trachoma natural history, such as an increasing rate of recovery from infection and a decreasing chlamydial load with subsequent infections that depend upon a (presumed) acquired immunity that clears infection with age more rapidly. Parameters were estimated using maximum likelihood by fitting the model to pre-control infection prevalence data from hypo-, meso- and hyperendemic communities from The Gambia and Tanzania. The model reproduces key features of trachoma epidemiology: 1) the age-profile of infection prevalence, which increases to a peak at very young ages and declines at older ages; 2) a shift in this prevalence peak, toward younger ages in higher force of infection environments; 3) a raised overall profile of infection prevalence with higher force of infection; and 4) a rising profile, with age, of the prevalence of the ensuing severe sequelae (trachomatous scarring, trichiasis), as well as estimates of the number of infections that need to occur before these sequelae appear.Conclusions/significanceWe present a framework that is sufficiently comprehensive to examine the outcomes of the A (antibiotic) component of the SAFE strategy on disease. The suitability of the model for representing population-level patterns of infection and disease sequelae is discussed in view of the individual processes leading to these patterns.
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Project description: Not available
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Project description:BackgroundWe describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease ?-secretase, from the initial interaction with its C99 substrate to the final release of toxic A? peptides.ResultsThe C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest A?42/A?40 ratio is observed in pre-steady-state when A?40 is the dominant product. A?42 is produced after A?40, and therefore A?42 is not a precursor for A?40. The longer more hydrophobic A? products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of ?-secretase with its C99 substrate leads to 30% decrease in A?40 with concomitant increase in the longer A? products and A?42/A?40 ratio. To different degree the same changes in A? products can be observed with two mutations that lead to an early onset of AD, ?E9 and G384A. Four different lines of evidence show that ?-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, Notch?E substrate can activate or inhibit ?-secretase activity on C99 substrate. Multiple C99 molecules bound to ?-secretase can affect processive cleavages of the nascent A? catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded A?-bundles.ConclusionsGradual saturation of ?-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of ?-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded A?-bundles generated by ?-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis.
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Project description:Trachoma, the leading infectious cause of blindness, is caused by Chlamydia trachomatis (Ct), a bacterium of the phylum Chlamydiae. Recent investigations revealed the existence of additional families within the phylum Chlamydiae, also termed Chlamydia-like organisms (CLOs). In this study, the frequency of Ct and CLOs was examined in the eyes of healthy Sudanese (control) participants and those with trachoma (case). We tested 96 children (54 cases and 42 controls) and 93 adults (51 cases and 42 controls) using broad-range Chlamydiae and Ct-specific (omcB) real-time PCR. Samples positive by broad-range Chlamydiae testing were subjected to DNA sequencing. Overall Chlamydiae prevalence was 36%. Sequences corresponded to unclassified and classified Chlamydiae. Ct infection rate was significantly higher in children (31.5%) compared to adults (0%) with trachoma (p < 0.0001). In general, 21.5% of adults and 4.2% of children tested positive for CLOs (p = 0.0003). Our findings are consistent with previous investigations describing the central role of Ct in trachoma among children. This is the first study examining human eyes for the presence of CLOs. We found an age-dependent distribution of CLO DNA in human eyes with significantly higher positivity in adults. Further studies are needed to understand the impact of CLOs in trachoma pathogenicity and/or protection.
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