Genome-wide scans for evidence of selection therefore have the ability to highlight important, previously uncharacterized genes

Genome-wide scans for evidence of selection therefore have the ability to highlight important, previously uncharacterized genes. Seventeen of the genes under selection are known to be immunogenic; this supports immune-recognition as a key driving factor of selection within this populace of ocular Ct samples. There was evidence of positive and purifying selection across the genome, but little balancing selection. In contrast, most antigens that were associated with susceptibility were under neutral selection. These data suggest an evasion strategy in which Ct presents a large panel of irrelevant antigens to the immune system to block or misdirect protective responses. Development of a focused immune response, possibly induced through vaccination, may be an effective strategy to promote protection to Ct contamination. Introduction Ocular contamination with (Ct) causes trachoma, the leading infectious cause of blindness1. Both ocular Ct contamination and active disease prevalence decline from their peaks in pre-school children (one to four years old) to older children (five to fourteen years old) and from this group to adults (fifteen years or older)2, 3. This suggests that partial Ct immunity evolves with increasing age in endemic communities, notwithstanding reduced exposure to Ct with increasing age4. Conjunctival Ct contamination induces a strong pro-inflammatory response marked by production of cytokines5, recruitment of neutrophils, macrophages and NK-cells6, 7. Induction and proliferation of CD4+ T-cells and production of interferon-gamma (IFN) have been implicated in successful resolution of contamination in animal models and human infections8C11. Ocular Ct contamination additionally induces local and systemic antibodies12. Neutralising antibodies against Ct have been demonstrated in animal models13 and remains unclear. Screening whole-proteome arrays has become an effective method to describe the complete profile of antibody responses in contamination and disease16. Studies utilising these proteome arrays have highlighted some common themes in humoral immune targets of human pathogens including functions in protein binding and catalytic activities, early or late expression in the developmental cycle and membrane localisation17. Genome-wide analyses of the type or mechanisms of selection have been conducted on a number of human pathogens and recognized known and novel targets that were under immune selective pressures. Studies in many human pathogens, including was under purifying (selection against deleterious alleles) and positive selection; comparable variance in selection pressure has been found in urogenital Ct sequences31. A lack of balancing selection in this immunodominant antigen, which is a target of neutralising antibodies, is usually in contrast to other pathogens and highlights the need for further population-based studies of Ct-genes under selection to better understand the interactions between Ct and the host GSK2200150A immune system. We PTGFRN used sera, collected from Gambian children at the baseline point of a six-month longitudinal cohort, to screen a protein microarray of 894 genomic ORFs from serovar D Ct32. The complete profile of responses for each sample was decided and used to investigate the differential acknowledgement of individual antigens and estimate the diversity and evenness of the antibody response associated with the frequency and duration of Ct contamination. A populace of 126 total genome sequences of ocular Ct samples obtained from discrete communities of four Bijagos Islands (Guinea-Bissau) collected in a single survey33, 34 was used in assessments of populace genetic selection. Genome-wide evidence of selection and genome-wide screening of the antibody response in the context of susceptibility to ocular contamination observed over a 6-month period were overlaid. This enabled us to identify new targets of humoral immunity and we uncovered two complementary immune evasion techniques that may support Ct survival and promote recurrent infection. Results Immunity defined by susceptibility to contamination After normalisation and filtering to remove infrequently recognised antigens, responses of 90 individuals covering 441 antigens were included in the analysis. Individuals were divided into those resistant or susceptible based on observed median period of infections over the six-month study period (Supplementary Physique?1). The study-wide median duration of contamination was 2 weeks (or one visit). Those with no infections or short period infections were combined (2 weeks; resistant) and compared to those with long duration infections ( 2 weeks; susceptible). The demographic similarity of resistant and susceptible individuals indicated that history of ocular Ct exposure was comparable (Table?1). Table 1 Age, gender and village membership in resistant and susceptible groups screened around the micro-array. and family members and a region within the Ct plasticity zone. Open in a separate window Physique 3 Evidence of positive selection using the integrated haplotype score. Genes in the top 1% of values (dashed red collection) experienced the strongest evidence of positive selection. Regions (blue lines) and individual SNPs (blue shading) under positive selection are indicated. GSK2200150A GSK2200150A Ct genes important GSK2200150A for Ct survival and pathogenesis were the focus of natural selection In this populace of ocular Ct samples, 48 genes were identified with evidence of selection by either a combination of Tajimas D GSK2200150A and Fay and Wus H, at the gene or epitope level, or by iHS. Expression stage of these genes and localisation of the.