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Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection.

ABSTRACT: 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, Chlamydia trachomatis, stimulates an acute host response. The main clinical feature is a follicular conjunctivitis that is incompletely defined at the tissue-specific gene expression and molecular levels. To explore the features of disease and the response to infection, we measured host gene expression in conjunctival samples from Gambian children with active trachoma and healthy controls. Genome-wide expression and transcription network analysis identified signatures characteristic of the expected infiltrating immune cell populations, such as neutrophils and T/B lymphocytes. The expression signatures were also significantly enriched for genes in pathways which regulate NK cell activation and cytotoxicity, antigen processing and presentation, chemokines, cytokines, and cytokine receptors. The data suggest that in addition to polymorph and adaptive cellular responses, NK cells may contribute to a significant component of the conjunctival inflammatory response to chlamydial infection.

SUBMITTER: Natividad A

PROVIDER: S-EPMC2976339 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection.

Natividad Angels A Freeman Tom C TC Jeffries David D Burton Matthew J MJ Mabey David C W DC Bailey Robin L RL Holland Martin J MJ

Infection and immunity 20100907 11

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, Chlamydia trachomatis, stimulates an acute host response. The main clinical feature is a follicular conjunctivitis that is incompletely defined at the tissu ...[more]

PMID: 20823212

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Project description:BackgroundClinical signs of active (inflammatory) trachoma are found in many children in the Solomon Islands, but the majority of these individuals have no serological evidence of previous infection with Chlamydia trachomatis. In Temotu and Rennell and Bellona provinces, ocular infections with C. trachomatis were seldom detected among children with active trachoma; a similar lack of association was seen between active trachoma and other common bacterial and viral causes of follicular conjunctivitis. Here, we set out to characterise patterns of gene expression at the conjunctivae of children in these provinces with and without clinical signs of trachomatous inflammation-follicular (TF) and C. trachomatis infection.MethodsPurified RNA from children with and without active trachoma was run on Affymetrix GeneChip Human Transcriptome Array 2.0 microarrays. Profiles were compared between individuals with ocular C. trachomatis infection and TF (group DI; n = 6), individuals with TF but no C. trachomatis infection (group D; n = 7), and individuals without TF or C. trachomatis infection (group N; n = 7). Differential gene expression and gene set enrichment for pathway membership were assessed.ResultsConjunctival gene expression profiles were more similar within-group than between-group. Principal components analysis indicated that the first and second principal components combined explained almost 50% of the variance in the dataset. When comparing the DI group to the N group, genes involved in T-cell proliferation, B-cell signalling and CD8+ T cell signalling pathways were differentially regulated. When comparing the DI group to the D group, CD8+ T-cell regulation, interferon-gamma and IL17 production pathways were enriched. Genes involved in RNA transcription and translation pathways were upregulated when comparing the D group to the N group.ConclusionsGene expression profiles in children in the Solomon Islands indicate immune responses consistent with bacterial infection when TF and C. trachomatis infection are concurrent. The transcriptomes of children with TF but without identified infection were not consistent with allergic or viral conjunctivitis.

Project description:BackgroundTrachoma, caused by ocular infection with Chlamydia trachomatis, remains the leading infectious cause of blindness and in 2002 was responsible for 3.6% of total global blindness. Although transmission can be successfully interrupted using antibiotics and improvements in public and personal hygiene, the long-term success of the control programmes advocated by the World Health Organization are still uncertain. For the complete control and prevention of trachoma, a vaccine would be highly desirable. Currently there are no licensed vaccines for trachoma, and no human vaccine trials have been conducted since the 1960s. A barrier to new attempts to design and introduce a vaccine is the identification of immunologic correlates of protective immunity or immunopathology. We studied important correlates of the immune response in a trachoma-endemic population in order to improve our knowledge of this disease. This is essential for the successful development of a vaccine against both ocular and genital C. trachomatis infection.Methods and findingsWe used quantitative real-time PCR for C. trachomatis 16S rRNA to identify conjunctival infection. The expression of IFN-gamma, IDO, IL-10, and FOXP3 mRNA transcripts was measured. We evaluated the role of immune effector and regulatory responses in the control of chlamydial infection and in the resolution of clinical signs of trachoma in endemic communities in Gambia. All host transcripts examined were detectable even in normal conjunctiva. The levels of these transcripts were increased, compared to normal uninfected conjunctiva, when infection was detected, with or without clinical disease signs. Interestingly, when clinical disease signs were present in the absence of infection, the expression of a regulatory T cell transcription factor, FOXP3, remained elevated.ConclusionsThere is evidence of an increase in the magnitude of the local anti-chlamydial cytokine immune responses with age. This increase is coupled to a decline in the prevalence of infection and active trachoma, suggesting that effective adaptive immunity is acquired over a number of years. The anti-chlamydial and inflammatory immune response at the conjunctival surface, which may control chlamydial replication, is closely matched by counter inflammatory or regulatory IL-10 expression. Differences in the level of FOXP3 expression in the conjunctiva may indicate a role for regulatory T cells in the resolution of the conjunctival immune response, which is important in protection from immunopathology. However, the expression of cytokines that control chlamydial replication and those that regulate the conjunctival immune response is not simply juxtaposed; the interaction between the infection and the clinical disease process is therefore more complex.

Project description:BackgroundTrachoma, a preventable blinding eye disease, is initiated by ocular infection with Chlamydia trachomatis (Ct). We previously showed that microRNAs (miR) -147b and miR-1285 were up-regulated in inflammatory trachomatous scarring. During the initial stage of disease, follicular trachoma with current Ct infection, the differential expression of miR has not yet been investigated.MethodsConjunctival samples were collected from 163 children aged 1-9 years old living in a trachoma-endemic region of Guinea Bissau, West Africa. Small RNA sequencing (RNAseq) was carried out on samples from five children with follicular trachoma and current Ct infection and five children with healthy conjunctivae and no Ct infection. Small RNAseq was also carried out on human epithelial cell lines infected with ocular Ct strains A2497 and isogenic plasmid-free A2497 in vitro. Results were validated by quantitative PCR (qPCR) in 163 clinical samples.ResultsDifferential expression of RNAseq data identified 12 miR with changes in relative expression during follicular trachoma, of which 9 were confirmed as differentially expressed by qPCR (miR-155, miR-150, miR-142, miR-181b, miR-181a, miR-342, miR-132, miR-4728 and miR-184). MiR-155 and miR-184 expression had a direct relationship with the degree of clinical inflammation. MiR-155 was up-regulated (OR = 2.533 ((95 % CI = 1.291-4.971); P = 0.0069) and miR-184 was down-regulated (OR = 0.416 ((95 % CI = 0.300-0.578); P = 1.61*10(-7)) as the severity of clinical inflammation increased. Differential miR expression was not detected in HEp-2 or HCjE epithelial cells 48 h post infection with Ct in vitro. HCjE cells, a conjunctival epithelial cell line, had a markedly different miR background expression compared to HEp-2 cells.ConclusionsIn follicular trachoma, expression of miR-155 and miR-184 is correlated with the severity of inflammation. This likely reflects host regulation of the immune response and a prolonged period of wound healing following the clearance of Ct. Prolonged healing may be associated with subsequent development of scarring trachoma.

Project description:This data comes from a genome-wide association study in 1090 cases of scarring trachoma and 1531 controls from a non-selected multi-ethnic sampling of The Gambia. The data constitutes hard base calls at 1457295 features from the HumanOmni2.5-8 (Omni2.5) BeadChip. Three genotype-calling algorithms were used : Illuminus (Bioinformatics 2007, 23:2741–6), GenCall (Patent US7035740, 2006) and GenoSNP (Bioinformatics 2008, 24:2209–14). Data from each calling algorithm was filtered to retain only SNPs with a call rate ≥ 0.98. To obtain a merged set of SNPs, all genotypes that matched across call-sets were retained, whilst those that mismatched between call-sets were set to missing. Genotypes that were present in one call set and missing in others were also retained. The merged SNP set contained 1467876 SNPs, which were filtered for call rate ≥ 0.99 and Hardy-Weinberg equilibrium P value < 5 x 10-8. The case and control groups were approximately equivalent with respect to gender and ethnicity. 70% of cases and 63% of controls were female. Self-described ethnic composition of the cases was 29% Jola, 27% Mandinka, 21% Wolof, 10% Fula and 13% other/no data. In controls the composition was 25% Jola, 24% Mandinka, 21% Wolof, 8% Fula and 22% other/no data. Median age was 49 (range 32-60) in cases and 37 (range 12-52) in controls (t = -3.6019, P = 0.0003). This data set has substantial levels of population structure, which reflects extensive networks of pairwise kinship between participants. First pass tests of association in EMMAX (Nat Genet 2010, 42:348–54) led to genome-wide deflation of the test statistics (λ = 0.982 SE = 1.74e-05) that could be directly attributed to the differing age and gender distributions between cases and controls. Modelling the phenotype to adjust for age and gender successfully controlled for this and no genome-wide deviation from the null was subsequently observed (λ = 1.001, SE = 8.7 x 10-7). Neither principal components analysis (PCA) nor tests of proportional identity by state (IBS) variance in PLINK identified significant levels of within or between group genetic variance. The phenotypes submitted in the phenotypes file include both uncorrected (case/control status) and corrected (age and gender corrected case/control status) phenotypes, as well as age and self-described ethnicity.

Dataset Information

Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection.

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Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection.

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