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Chlamydia trachomatis Strain Types Have Diversified Regionally and Globally with Evidence for Recombination across Geographic Divides.

ABSTRACT: Chlamydia trachomatis (Ct) is the leading cause of bacterial sexually transmitted diseases worldwide. The Ct Multi Locus Sequence Typing (MLST) scheme is effective in differentiating strain types (ST), deciphering transmission patterns and treatment failure, and identifying recombinant strains. Here, we analyzed 323 reference and clinical samples, including 58 samples from Russia, an area that has not previously been represented in Ct typing schemes, to expand our knowledge of the global diversification of Ct STs. The 323 samples resolved into 84 unique STs, a 3.23 higher typing resolution compared to the gold standard single locus ompA genotyping. Our MLST scheme showed a high discriminatory index, D, of 0.98 (95% CI 0.97-0.99) confirming the validity of this method for typing. Phylogenetic analyses revealed distinct branches for the phenotypic diseases of lymphogranuloma venereum, urethritis and cervicitis, and a sub-branch for ocular trachoma. Consistent with these findings, single nucleotide polymorphisms were identified that significantly correlated with each phenotype. While the overall number of unique STs per region was comparable across geographies, the number of STs was greater for Russia with a significantly higher ST/sample ratio of 0.45 (95% CI: 0.35-0.53) compared to Europe or the Americas (p < 0.009), which may reflect a higher level of sexual mixing with the introduction of STs from other regions and/or reassortment of alleles. Four STs were found to be significantly associated with a particular geographic region. ST23 [p = 0.032 (95% CI: 1-23)], ST34 [p = 0.019 (95% CI: 1.1-25)]; and ST19 [p = 0.001 (95% CI: 1.7-34.7)] were significantly associated with Netherlands compared to Russia or the Americas, while ST 30 [p = 0.031 (95% CI: 1.1-17.8)] was significantly associated with the Americas. ST19 was significantly associated with Netherlands and Russia compared with the Americans [p = 0.001 (95% CI: 1.7-34.7) and p = 0.006 (95% CI: 1.5-34.6), respectively]. Additionally, recombinant strains were ubiquitous in the data set [106 (32.8%)], although Europe had a significantly higher number than Russia or the Americas (p < 0.04), the majority of which were from Amsterdam [43 (87.8%) of 49)]. The higher number of recombinants in Europe indicates selective pressure and/or adaptive diversification that will require additional studies to elucidate.

SUBMITTER: Smelov V

PROVIDER: S-EPMC5693916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chlamydia trachomatis is an obligate intracellular bacterial parasite, which causes several severe and debilitating diseases in humans. This study uses comparative genomic analyses of 12 complete published C. trachomatis genomes to assess the contribution of recombination and selection in this pathogen and to understand the major evolutionary forces acting on the genome of this bacterium.The conserved core genes of C. trachomatis are a large proportion of the pan-genome: we identified 836 core genes in C. trachomatis out of a range of 874-927 total genes in each genome. The ratio of recombination events compared to mutation (?/?) was 0.07 based on ancestral reconstructions using the ClonalFrame tool, but recombination had a significant effect on genetic diversification (r/m=0.71). The distance-dependent decay of linkage disequilibrium also indicated that C. trachomatis populations behaved intermediately between sexual and clonal extremes. Fifty-five genes were identified as having a history of recombination and 92 were under positive selection based on statistical tests. Twenty-three genes showed evidence of being under both positive selection and recombination, which included genes with a known role in virulence and pathogencity (e.g., ompA, pmps, tarp). Analysis of inter-clade recombination flux indicated non-uniform currents of recombination between clades, which suggests the possibility of spatial population structure in C. trachomatis infections.C. trachomatis is the archetype of a bacterial species where recombination is relatively frequent yet gene gains by horizontal gene transfer (HGT) and losses (by deletion) are rare. Gene conversion occurs at sites across the whole C. trachomatis genome but may be more often fixed in genes that are under diversifying selection. Furthermore, genome sequencing will reveal patterns of serotype specific gene exchange and selection that will generate important research questions for understanding C. trachomatis pathogenesis.This article was reviewed by Dr. Jeremy Selengut, Dr. Lee S. Katz (nominated by Dr. I. King Jordan) and Dr. Arcady Mushegian.

Project description:The large number of sexually transmitted diseases and ocular trachoma cases that are caused globally each year by Chlamydia trachomatis has made this organism a World Health Organization priority for vaccine development. However, there is no gene transfer system for Chlamydia to help identify potential vaccine targets. To accelerate discoveries toward this goal, here we analyzed the broadest diversity of C. trachomatis genomes to date, including 25 geographically dispersed clinical and seven reference strains representing 14 of the 19 known serotypes. Strikingly, all 32 genomes were found to have evidence of DNA acquisition by homologous recombination in their history. Four distinct clades were identified, which correspond to all C. trachomatis disease phenotypes: lymphogranuloma venereum (LGV; Clade 1); noninvasive urogenital infections (Clade 2); ocular trachoma (Clade 3); and protocolitis (Clade 4; also includes some noninvasive urogenital infections). Although the ancestral relationship between clades varied, most strains acted as donor and recipient of recombination with no evidence for barriers to genetic exchange. The niche-specific LGV and trachoma clades have undergone less recombination, although the opportunity for mixing with strains from other clades that infect the rectal and ocular mucosa, respectively, is evident. Furthermore, there are numerous occasions for gene conversion events through sequential infections at the same anatomic sites. The size of recombinant segments is relatively small (~357 bp) compared with in vitro experiments of various C. trachomatis strains but is consistent with in vitro estimates for other bacterial species including Escherichia coli and Helicobacter pylori. Selection has also played a crucial role during the diversification of the organism. Clade 2 had the lowest nonsynonymous to synonymous ratio (dN/dS) but the highest effect of recombination, which is consistent with the widespread occurrence of synonymous substitutions in recombined genomic segments. The trachoma Clade 3 had the highest dN/dS estimates, which may be caused by an increased effect of genetic drift from niche specialization and a reduced effective population size. The degree of drift, selection, and recombination in C. trachomatis suggests that the challenge will remain to identify genomic regions that are stable and cross protective for the development of an efficacious vaccine.

Project description:UnlabelledIntracellular bacterial pathogens in the family Chlamydiaceae are causes of human blindness, sexually transmitted disease, and pneumonia. Genetic dissection of the mechanisms of chlamydial pathogenicity has been hindered by multiple limitations, including the inability to inactivate genes that would prevent the production of elementary bodies. Many genes are also Chlamydia-specific genes, and chlamydial genomes have undergone extensive reductive evolution, so functions often cannot be inferred from homologs in other organisms. Conditional mutants have been used to study essential genes of many microorganisms, so we screened a library of 4,184 ethyl methanesulfonate-mutagenized Chlamydia trachomatis isolates for temperature-sensitive (TS) mutants that developed normally at physiological temperature (37°C) but not at nonphysiological temperatures. Heat-sensitive TS mutants were identified at a high frequency, while cold-sensitive mutants were less common. Twelve TS mutants were mapped using a novel markerless recombination approach, PCR, and genome sequencing. TS alleles of genes that play essential roles in other bacteria and chlamydia-specific open reading frames (ORFs) of unknown function were identified. Temperature-shift assays determined that phenotypes of the mutants manifested at distinct points in the developmental cycle. Genome sequencing of a larger population of TS mutants also revealed that the screen had not reached saturation. In summary, we describe the first approach for studying essential chlamydial genes and broadly applicable strategies for genetic mapping in Chlamydia spp. and mutants that both define checkpoints and provide insights into the biology of the chlamydial developmental cycle.ImportanceStudy of the pathogenesis of Chlamydia spp. has historically been hampered by a lack of genetic tools. Although there has been recent progress in chlamydial genetics, the existing approaches have limitations for the study of the genes that mediate growth of these organisms in cell culture. We used a genetic screen to identify conditional Chlamydia mutants and then mapped these alleles using a broadly applicable recombination strategy. Phenotypes of the mutants provide fundamental insights into unexplored areas of chlamydial pathogenesis and intracellular biology. Finally, the reagents and approaches we describe are powerful resources for the investigation of these organisms.

Project description:BackgroundThis is the first report to characterize the prevalence and genovar distribution of genital chlamydial infections among random heterosexual patients in the multi-ethnic Saratov Region, located in Southeast Russia.MethodsSixty-one clinical samples (cervical or urethral swabs) collected from a random cohort of 856 patients (7.1%) were C. trachomatis (CT) positive in commercial nucleic acid amplification tests (NAATs) and duplex TaqMan PCRs.ResultsSequence analysis of the VDII region of the ompA gene revealed seven genovars of C. trachomatis in PCR-positive patients. The overall genovars were distributed as E (41.9%), G (21.6%), F (13.5%), K (9.5%), D (6.8%), J (4.1%), and H (2.7%). CT-positive samples were from males (n = 12, 19.7%), females (n = 42, 68.8%), and anonymous (n = 7, 11.5%) patients, with an age range of 19 to 45 years (average 26.4), including 12 different ethnic groups representative of this region. Most patients were infected with a single genovar (82%), while 18% were co-infected with either two or three genovars. The 1156 bp-fragment of the ompA gene was sequenced in 46 samples to determine single nucleotide polymorphisms (SNP) among isolates. SNP-based subtyping and phylogenetic reconstruction revealed the presence of 13 variants of the ompA gene, such as E (E1, E2, E6), G (G1, G2, G3, G5), F1, K, D (D1, Da2), J1, and H2. Differing genovar distribution was identified among urban (E>G>F) and rural (E>K) populations, and in Slavic (E>G>D) and non-Slavic (E>G>K) ethnic groups. Multilocus sequence typing (MLST) determined five sequences types (STs), such as ST4 (56%, 95% confidence interval, CI, 70.0 to 41.3), ST6 (10%, 95% CI 21.8 to 3.3), ST9 (22%, 95% CI 35.9 to 11.5), ST10 (2%, 95% CI 10.7 to 0.05) and ST38 (10%, 95% CI 21.8 to 3.3). Thus, the most common STs were ST4 and ST9.ConclusionC. trachomatis is a significant cause of morbidity among random heterosexual patients with genital chlamydial infections in the Saratov Region. Further studies should extend this investigation by describing trends in a larger population, both inside and outside of the Saratov Region to clarify some aspects for the actual application of C. trachomatis genotype analysis for disease control.

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Chlamydia trachomatis Strain Types Have Diversified Regionally and Globally with Evidence for Recombination across Geographic Divides.

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