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(a) Similarity of global gene expression clusters samples into three distinct groups. The axes of the matrix are clustered with a simple tree, which represents sample distance based on the global similarity of gene expression (sample-to-sample Pearson correlation coefficient). The trachoma clinical grading and infection scores are shown on the right hand side (F, follicular score; P, papillary hypertrophy score; Amplicor, C. trachomatis PCR positive or negative; C. trachomatis load, qPCR estimate of the number of C. trachomatis ompA copies per swab). The genome-wide expression profiles of conjunctival tissue from 60 Gambian subjects resident in communities where trachoma is endemic were used to construct the 60-by-60 matrix. The expression across all 54,675 probe sets on the HG-U133 plus 2.0 GeneChip were used. Three main branches (1, 2, and 3) cluster the samples into groups based on the biological signature of their overall gene expression profile. Samples defined by a branch share the greatest similarity with each other. Overall, the separation achieved by the unsupervised clustering of the samples has a true class accuracy value of 70% and implies that the three groups have a different expression signature. (b) Sample-to-sample correlation network represented in BioLayout Express3D. A matrix file was generated by comparing the overall expression pattern of all samples (as in panel a) and used to generate a graph of the data. In this context, nodes represent samples and the edges correlation values between them greater than the selected threshold (r = 0.95). The thicker/redder is the edge, the higher is the sample-to-sample correlation that it represents. Panel A, nodes colored light blue represent samples derived from healthy participants showing no clinical signs of disease or infection, those colored green represent participants who had clinical signs of disease but no detectable infection, and those colored red represent participants with clinical signs of disease and C. trachomatis infection. Panel B, nodes colored gray represent samples derived from participants showing no detectable levels of infection, those in yellow represent those with C. trachomatis loads of <34 copies per swab, those in green represent C. trachomatis loads of 34 to 389, and those in red represent loads f >390. Panel C, nodes colored gray represent participants with an F score of 0, those colored blue represent participants with an F score of 2, and those colored maroon represent participants with an F score of 3. Panel D, nodes colored gray represent participants with a P score of 0, those colored green represent participants with a P score of 1, those colored blue represent participants with a P score of 2, and those colored maroon represent participants with a P score of 3.
Source publication
Trachoma is the leading infectious cause of blindness and is endemic in 52 countries. There is a critical need to further
our understanding of the host response during disease and infection, as millions of individuals are still at risk of developing
blinding sequelae. Infection of the conjunctival epithelial cells by the causative bacterium, Chlamy...
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Citations
... Transcriptomic datasets GSE20436, GSE20430 [18], GSE114556 [19], GSE105149 [20], GSE180238 [21] and GSE180027 [22] were downloaded from the NCBI Gene Expression Omnibus using the Bioconductor R package GEOquery. If not already, datasets were logtransformed, and quantile-normalised using the preprocessCore R package. ...
... Based on this screen CXCL1, IP-10, IFN-γ, IL-1β, IL-8, IL-10, IL-12 p40, IL1-RA and IL-1α were selected for follow up multiplex cytokine assays on individual Tanzanian samples. IL-27 was not selected for further follow up due to lack of differential expression in microarray data [18]. PDGF-AB/BB, while not included in the semi-quantitative array, was selected for inclusion in the multiplex cytokine assay since it has previously been associated with conjunctival damage [24]. ...
... While there were too few participants with active trachoma (clinical grades F > 1, P > 2, n = 2) to detect changes in active disease, IL-10, IL-8 and CXCL1 were significantly increased in those with clinical grades F > 0 or P > 0 (p = 0.0031, 0.014, 0.037 respectively, logistic regression). Consistently, re-analysis of a gene expression array performed in a cross-sectional Gambian study independent of the samples assayed in this study [18] identified the genes encoding IL-10, IL-8 and CXCL1 as being upregulated (p < 0.05, linear modelling) during active disease (Table A in S1 Text). ...
Background
Trachoma is a neglected tropical disease caused by ocular infection with Chlamydia trachomatis , where repeated infections and chronic inflammation can ultimately result in scarring, trichiasis and blindness. While scarring is thought to be mediated by a dysregulated immune response, the kinetics of cytokines and antimicrobial proteins in the tear film have not yet been characterised.
Methodology
Pooled tears from a Gambian cohort and Tanzanian cohort were semi-quantitatively screened using a Proteome Profiler Array to identify cytokines differentially regulated in disease. Based on this screen and previous literature, ten cytokines (CXCL1, IP-10, IFN-γ, IL-1β, IL-8, IL-10, IL-12 p40, IL-1RA, IL-1α and PDGF), lysozyme and lactoferrin were assayed in the Tanzanian cohort by multiplex cytokine assay and ELISA. Finally, CXCL1, IP-10, IL-8, lysozyme and lactoferrin were longitudinally profiled in the Gambian cohort by multiplex cytokine assay and ELISA.
Results
In the Tanzanian cohort, IL-8 was significantly increased in those with clinically inapparent infection (p = 0.0086). Lysozyme, IL-10 and chemokines CXCL1 and IL-8 were increased in scarring (p = 0.016, 0.046, 0.016, and 0.037). CXCL1, IP-10, IL-8, lysozyme and lactoferrin were longitudinally profiled over the course of infection in a Gambian cohort study, with evidence of an inflammatory response both before, during and after detectable infection. CXCL1, IL-8 and IP-10 were higher in the second infection episode relative to the first (p = 0.0012, 0.044, and 0.04).
Conclusions
These findings suggest that the ocular immune system responds prior to and continues to respond after detectable C . trachomatis infection, possibly due to a positive feedback loop inducing immune activation. Levels of CXC chemokines in successive infection episodes were increased, which may offer an explanation as to why repeated infections are a risk factor for scarring.
... Based on this screen CXCL1, IP10, IFN-γ, IL1β, IL8, IL10, IL12p40, IL1RA and IL1α were selected for follow up multiplex cytokine assays on individual Tanzanian samples. IL27 was not selected for further follow up due to lack of differential expression in microarray data (17). PDGF-AB/BB, while not included in the semi-quantitative array, was selected for inclusion in the multiplex cytokine assay since it has previously been associated with conjunctival damage (23). ...
... While there were too few participants with active trachoma (clinical grades F > 1, P > 2, n = 2) to detect changes in active disease, IL10, IL1β, IL8 and CXCL1 were raised in those with clinical grades F > 0 or P > 0 (p = 0.0031, 0.097, 0.014, 0.037 respectively, logistic regression). Consistently, re-analysis of a gene expression array performed in a cross-sectional Gambian study independent of the samples assayed in this study (17) identi ed the genes encoding IL10, IL1β, IL8 and CXCL1 as being upregulated (p < 0.05, linear modelling) during active disease (Additional le 2: Table S1). ...
... However, in the Tanzanian cohort IL10, IL1β, IL8 and CXCL1 were raised in those with clinical grades F > 0 or P > 0 (p < 0.05), while in the Gambian cohort there was a trend towards greater IL8 and CXCL1 in active disease (p < 0.15). This is consistent with transcriptomic arrays nding a rise in conjunctival IL10, IL1B, IL8 and CXCL1 mRNA (17), quantitative PCR nding a rise in conjunctival IL1B and IL10 mRNA (34), and cytokine assays nding a rise in tear IL8 and IL10 (14) during active disease. ...
Background
Trachoma is a neglected tropical disease caused by ocular infection with Chlamydia trachomatis, where repeated infections and chronic inflammation can ultimately result in scarring, trichiasis and blindness. While scarring is thought to be mediated by a dysregulated immune response, the kinetics of cytokines and antimicrobial proteins in the tear film have not yet been characterised.
Methods
Pooled tears from a Gambian cohort and Tanzanian cohort were semi-quantitatively screened using a Proteome Profiler Array to identify cytokines differentially regulated in disease. Based on this screen and previous literature, ten cytokines (CXCL1, IP10, IFN-γ, IL1β, IL8, IL10, IL12p40, IL1RA, IL1α and PDGF), lysozyme and lactoferrin were assayed in the Tanzanian cohort by multiplex cytokine assay and ELISA. Finally, CXCL1, IP10, IL8, lysozyme and lactoferrin were longitudinally profiled in the Gambian cohort by multiplex cytokine assay and ELISA.
Results
In the Tanzanian cohort, IL8 was significantly raised in those with clinically inapparent infection (p = 0.0086). Lysozyme, IL10 and chemokines CXCL1, IL8, and IP10 were raised in scarring (p = 0.016, 0.046, 0.016, 0.037 and 0.093). CXCL1, IP10, IL8, lysozyme and lactoferrin were longitudinally profiled over the course of infection in a Gambian cohort study, with evidence of an inflammatory response both before, during and after detectable infection. CXCL1, IL8 and IP10 were raised in the second infection episode relative to the first (p = 0.0012, 0.044, and 0.04).
Conclusions
These findings suggest that the ocular immune system responds prior to and continues to respond after detectable C. trachomatis infection, possibly due to a positive feedback loop inducing immune activation. Levels of CXC chemokines in successive infection episodes were increased, which may offer an explanation as to why repeated infections are a risk factor for scarring.
... In vitro infection studies of epithelial cells have found a marked innate proinflammatory response, with the production of several cytokines: IL6, IL8, growthregulated oncogeneα (GROα) and granulocytemacrophage colonystimulating factor (GMCSF) 100,101 ( fig. 3). This finding is consistent with data from in vivo investigations into conjunctival gene expression profiles using swabs taken from the conjunctival surface [102][103][104][105] . The initial innate response to Ct is likely to be driven directly by infected epithelial cells, recognizing the pres ence of the organism through their patternrecognition receptors, leading to a chronic inflammatory response. ...
... Resolution of Ct infection is thought to be depend ent on IFNγ from a CD4 + T helper 1 (T H 1) cellmediated immune response. Gene expression studies in children in trachomaendemic populations show a marked increase in conjunctival expression of IFNγ and T H 1 cellrelated factors (IL12B and indoleamine2,3dioxygenase (IDO1)) and in natural killer cell pathways (characterized by NCR1, CD56 and CD247) [102][103][104] . In children with active trachoma but no detectable Ct, levels of IFNγ are not par ticularly elevated, suggesting that this response is rapidly regulated following the resolution of infection. ...
Trachoma is a neglected tropical disease caused by infection with conjunctival strains of Chlamydia trachomatis. It can result in blindness. Pathophysiologically, trachoma is a disease complex composed of two linked chronic processes: a recurrent, generally subclinical infectious–inflammatory disease that mostly affects children, and a non-communicable, cicatricial and, owing to trichiasis, eventually blinding disease that supervenes in some individuals later in life. At least 150 infection episodes over an individual’s lifetime are needed to precipitate trichiasis; thus, opportunity exists for a just global health system to intervene to prevent trachomatous blindness. Trachoma is found at highest prevalence in the poorest communities of low-income countries, particularly in sub-Saharan Africa; in June 2021, 1.8 million people worldwide were going blind from the disease. Blindness attributable to trachoma can appear in communities many years after conjunctival C. trachomatis transmission has waned or ceased; therefore, the two linked disease processes require distinct clinical and public health responses. Surgery is offered to individuals with trichiasis and antibiotic mass drug administration and interventions to stimulate facial cleanliness and environmental improvement are designed to reduce infection prevalence and transmission. Together, these interventions comprise the SAFE strategy, which is achieving considerable success. Although much work remains, a continuing public health problem from trachoma in the year 2030 will be difficult for the world to excuse. Trachoma, caused by infection with conjunctival strains of Chlamydia trachomatis, is the most common infectious cause of blindness. This Primer summarizes the epidemiology, pathophysiology and diagnosis of trachoma as well as its management, disease control and elimination, and key areas for future research.
... The presence of neutrophils was also observed in C. trachomatisinfected human endocervical samples (3). Conjunctival samples taken from children with active trachoma also showed the expression of various genes that could be linked to neutrophils (4). While there are conflicting results concerning the role of neutrophils in suppressing Chlamydia growth (5), neutrophils are considered as being a major source of Chlamydia infectioninduced tissue damage and remodeling (6). ...
Aims
Neutrophil granulocytes are the major cells involved in Chlamydia trachomatis (C. trachomatis)-mediated inflammation and histopathology. A key protein in human intracellular antichlamydial defense is the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) which limits the growth of the tryptophan auxotroph Chlamydia. Despite its importance, the role of IDO in the intracellular defense against Chlamydia in neutrophils is not well characterized.
Methods
Global gene expression screen was used to evaluate the effect of C. trachomatis serovar D infection on the transcriptome of human neutrophil granulocytes. Tryptophan metabolite concentrations in the Chlamydia-infected and/or interferon-gamma (IFNG)-treated neutrophils were measured by ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS).
Results
Our results indicate that the C. trachomatis infection had a major impact on neutrophil gene expression, inducing 1,295 genes and repressing 1,510 genes. A bioinformatics analysis revealed that important factors involved in the induction of neutrophil gene expression were the interferon-related transcription factors such as IRF1-5, IRF7-9, STAT2, ICSB, and ISGF3. One of the upregulated genes was ido1, a known infection- and interferon-induced host gene. The tryptophan-degrading activity of IDO1 was not induced significantly by Chlamydia infection alone, but the addition of IFNG greatly increased its activity. Despite the significant IDO activity in IFNG-treated cells, C. trachomatis growth was not affected by IFNG. This result was in contrast to what we observed in HeLa human cervical epithelial cells, where the IFNG-mediated inhibition of C. trachomatis growth was significant and the IFNG-induced IDO activity correlated with growth inhibition.
Conclusions
IDO activity was not able to inhibit chlamydial growth in human neutrophils. Whether the IDO activity was not high enough for inhibition or other chlamydial growth-promoting host mechanisms were induced in the infected and interferon-treated neutrophils needs to be further investigated.
... Multiple studies have demonstrated an effect of MX protein in viral replication by interference with transcription and translation [58]. In addition, human studies have indicated induction of MX1 and MX2 in ocular Ct infection [59]. Based on the role in transcriptional and translational interference, MX1 and MX2 upregulation by pOECs could aim to limit Ct propagation and thereby Ct infection within the genital tract. ...
Chlamydia trachomatis (Ct) causes the most prevalent bacterial sexually transmitted disease leading to ectopic pregnancy and infertility. Swine not only have many similarities to humans, but they are also susceptible to Ct. Despite these benefits and the ease of access to primary tissue from this food animal, in vitro research in swine has been underutilized. This study will provide basic understanding of the Ct host–pathogen interactions in porcine oviduct epithelial cells (pOECs)—the counterparts of human Fallopian tube epithelial cells. Using NanoString technology, flow cytometry, and confocal and transmission-electron microscopy, we studied the Ct developmental cycle in pOECs, the cellular immune response, and the expression and location of the tight junction protein claudin-4. We show that Ct productively completes its developmental cycle in pOECs and induces an immune response to Ct similar to human cells: Ct mainly induced the upregulation of interferon regulated genes and T-cell attracting chemokines. Furthermore, Ct infection induced an accumulation of claudin-4 in the Ct inclusion with a coinciding reduction of membrane-bound claudin-4. Downstream effects of the reduced membrane-bound claudin-4 expression could potentially include a reduction in tight-junction expression, impaired epithelial barrier function as well as increased susceptibility to co-infections. Thereby, this study justifies the investigation of the effect of Ct on tight junctions and the mucosal epithelial barrier function. Taken together, this study demonstrates that primary pOECs represent an excellent in vitro model for research into Ct pathogenesis, cell biology and immunity.
... Transcriptional profiling of trachoma conjunctival samples showed transcriptional networks connected to the innate immune response 10,11 . Biomarker studies of women with chlamydial endometritis found increased expression levels of myeloid cellassociated inflammation 12 . ...
Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We find the chlamydial parasitophorous vacuole protein CT135 triggers NLRP3 inflammasome activation via TLR2/MyD88 signaling as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135 mediated neutrophil killing results in a submucosal macrophage-associated endometritis driven by ATP/P2X7R induced NLRP3 inflammasome activation. Importantly, macrophage-associated immunopathology occurs independent of macrophage infection. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP. We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis. Myeloid cells are implicated in the innate immune and inflammatory response during infection with Chlamydia trachomatis. Here the authors show the evasion of the neutrophil response to infection and concomitant induction of sterile immunity via the purinergic P2X7 receptor.
... The cellular structures (autologous, and/or contaminated cellular material) which are captured by the needle tip consequently can be injected into the vitreous cavity and have the potential to contaminate and proliferate inside the vitreous body. [26][27][28] There are a number of studies that analyze the causes of IVI-associated endophthalmitis and the mechanism of its development. 1,[29][30][31][32][33] Different ways for reduction of endophthalmitis risk have been proposed after IVI. ...
Purpose
To study the efficacy of a novel needle for intravitreal injection (IVI) in comparison to the conventional needle under experimental conditions.
Methods
The newly designed 30-gauge (G) needle (NDN) (EP 18158 542.3, patent pending) with occluded outer orifice and a side port for drug delivery was compared to the conventional standard hypodermic 30 G needle for IVI (SHN). An animal study to obtain needle tip aspirates was performed on 10 albino rat eyes. During IVIs, cellular content, which was cut by the needle tip, was aspirated. Cellular material was studied in regard to cell types and their quantity. The injection stream was studied using trypan blue dye in vitro and pig cadaver eyes. The penetration force was tested on polyurethane Testing Foil Strips PU 04 (Melab, Leonberg, Germany) by applying a velocity of 100 mm/min. The results were analyzed using descriptive statistics, correlation matrices and t-test methods with p<0.05 as statistically significant.
Results
Cytological analysis of the needle aspirates showed the presence of cellular content in each case. The amount of conjunctival, ciliary body epithelial cells and granulated basophilic protein sediments (sign of cellular damage) in the case of the NDN tips was significantly lower compared to the SHN. The average penetration force of the NDN was 0.791 N, and in the case of the SHN was 0.566 N. The injection stream study revealed a difference in the initial injection phase between the two needle types, although the diffuse filling of the vitreous area which surrounded the needle tip appeared to be similar.
Discussion
The NDN demonstrated superior performance with regard to a significantly reduced number of cells being captured by the needle tip. Delivery of the injected fluid into the vitreous cavity was comparable. In order to investigate superior properties of the NDN needle design, further studies with improved prototypes would be necessary.
... Innate immunity is implicated in the immunopathogenesis of trachoma and PID (33). Transcriptional profiling of trachoma conjunctival samples showed transcriptional networks connected to the innate immune response (42,43). Biomarker studies of women with chlamydial endometritis found increased expression levels of myeloid mediators of inflammation (44). ...
Chlamydia trachomatis can cause persistent infection that drives damaging inflammatory responses resulting in infertility and blindness. Little is known about chlamydial genes that cause persistence or factors that drive damaging pathology. In this work, we show that the C. trachomatis plasmid protein gene 3 (Pgp3) is the essential virulence factor for establishing persistent female genital tract infection and provide supportive evidence that Pgp3 functions similarly in a nonhuman primate trachoma model. We further show that persistent Ppg3-dependent infection drives damaging immunopathology. These results are important advances in understanding the pathophysiology of chlamydial persistence.
... The factors involved in the inflammatory responses to repeated Ct infection that lead to conjunctival scarring, trichiasis, corneal opacity and blindness remain poorly understood. In addition to Ct infection, other factors, including the type and quality of the conjunctival host immune responses (Holland et al., 2010;Natividad et al., 2010;Burton et al., 2011b;Ramadhani et al., 2017), host genetic background (Roberts et al., 2014b), infections with other ocular pathogens and changes in overall bacterial community composition (Burton et al., 2011a;Hu et al., 2011aHu et al., , 2018Zhou et al., 2014) have each been linked to the different stages of trachomatous disease. Thus far there have been a limited number of studies that have investigated the interaction between the nonchlamydial ocular microbiota and conjunctival immune response in trachoma Hu et al., 2012). ...
... In typical cases of active trachoma with proven Ct infection, such as reported in historical studies in The Gambia, the conjunctival response to Ct infection is characterized by epithelial cell reorganization, immune cell infiltration and secretion of anti-microbial peptides (Natividad et al., 2010). Similarly, trachomatous inflammation follicular (TF) and trachomatous scarring (TS) were also associated with expression of innate pro-inflammatory markers in Ethiopian and Tanzanian populations (Burton et al., 2011a,b;Hu et al., 2012;Ramadhani et al., 2017). ...
... Gene expression (GE) was characterized using TLDA Microfluidic Cards for targeted immune transcripts and qPCR for miRNA transcripts previously identified as associated with trachoma (Natividad et al., 2010;Burton et al., 2011b;Derrick et al., 2013Derrick et al., , 2016. GE data were available from 78/85 children (N = 32, AT = 46) and 147/279 adults (N = 69, ST = 78) (Supplementary Table 2). ...
Background: Trachoma, a neglected tropical disease, is the leading infectious cause of blindness and visual impairment worldwide. Host responses to ocular chlamydial infection resulting in chronic inflammation and expansion of non-chlamydial bacteria are hypothesized risk factors for development of active trachoma and conjunctival scarring. Methods: Ocular swabs from trachoma endemic populations in The Gambia were selected from archived samples for 16S sequencing and host conjunctival gene expression. We recruited children with active trachoma and adults with conjunctival scarring, alongside corresponding matched controls. Findings: In children, active trachoma was not associated with significant changes in the ocular microbiome. Haemophilus enrichment was associated with antimicrobial responses but not linked to active trachoma. Adults with scarring trachoma had a reduced ocular bacterial diversity compared to controls, with increased relative abundance of Corynebacterium. Increased abundance of Corynebacterium in scarring disease was associated with innate immune responses to the microbiota, dominated by altered mucin expression and increased matrix adhesion. Interpretation: In the absence of current Chlamydia trachomatis infection, changes in the ocular microbiome associate with differential expression of antimicrobial and inflammatory genes that impair epithelial cell health. In scarring trachoma, expansion of non-pathogenic bacteria such as Corynebacterium and innate responses are coincident, warranting further investigation of this relationship. Comparisons between active and scarring trachoma supported the relative absence of type-2 interferon responses in scarring, whilst highlighting a common suppression of re-epithelialization with altered epithelial and bacterial adhesion, likely contributing to development of scarring pathology.
... Studies using immortalized and primary genital epithelial cells support the hypothesis that the inflammatory response to C. trachomatis is initiated and perpetuated by epithelial cells (39,(57)(58)(59)(60)(61). The female reproductive tract is particularly susceptible to C. trachomatis infection of the columnar epithelium of the endocervix (62), and urogenital strains such as D and L 2 have been shown to induce the production of IL-1␣, IL-6, TNF-␣, IL-10, IL-12, and GM-CSF (reviewed in reference 17), contributing to an adverse inflammatory response (reviewed in reference 63). ...
Chlamydia trachomatis is a human pathogen and the leading cause of preventable blindness and sexually transmitted diseases in the world. Certain C. trachomatis strains cause ocular disease, while others cause upper genital tract pathology. However, little is known about the cellular or immunologic basis for these differences. Here, we compared the abilities of the strain types to infect, replicate, and initiate an immune response in primary human ocular and urogenital epithelial cells, as well as in fibroblasts from the underlying stroma. While there were no significant differences in infection rates or intracellular growth for any strain in any cell type, proinflammatory responses were driven not by the epithelial cells but by fibroblasts and were distinct between ocular and urogenital strains. Our findings suggest that primary fibroblasts are a novel and more appropriate model for studies of immune responses that will expand our understanding of the differential pathological disease outcomes caused by various C. trachomatis strain types.
