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Mar 12, 2012

Chlamydia Serotyping May Be Inaccurate Thanks to Widespread Bacterial Recombination

  • The ability of different Chlamydia trachomatis strains to exchange genetic information by recombination is much more comprehensive than previously believed, according to data from a comparative whole-genome sequencing project led by the Wellcome Trust Sanger Institute in the U.K. Data from the analyses have provided new insights into the evolution of C. trachomatis, and suggest that current diagnostics aren’t adequate to detect strain variations or determine whether repeat infections in an individual patient are caused by the same variant.  

    Nicholas R. Thomson, M.D., and colleagues describe their findings in Nature Genetics, in a paper titled “Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing.”

    Estimates suggest that C. trachomatis represents the most prevalent bacterial sexually transmitted disease worldwide, with some 101.5 million new cases emerging every year. In addition, ocular C. trachomatis is the most common infectious cause of blindness, with over 40 million people worldwide estimated to have active disease.

    C. trachomatis comprises two biovars: the trachoma biovar includes ocular and urogenital strains that cause localized epithelial infections of the conjunctiva or genital mucosa, while lymphogranuloma venereum (LGV) biovar strains can spread systemically throughout the lymphatic system.

    Current Chlamydia diagnostic methods are based on nucleic acid amplification, and the bulk of our understanding of the pathogen’s diversity has been gleaned from data on the bacterium’s primary surface antigen, the major outer membrane protein (MOMP), and its gene, ompA. Indeed typing of Chlamydia is generally carried out serologically using antibodies to divergent MOMP epitopes. More recent genotyping approaches using ompA have provided new insights, and further subdivision of the trachoma biovar and the LGV biovar.

    The Sanger team, along with researchers at the U.K’s University of Southampton and internationally, has now sequenced 36 C. trachomatis genomes from strains isolated over the last 40 years, including urinogenital, ocular, and LGV strains. Data from these they combined with those from 16 previously published LGV, ocular, and urogenital strains.

    Analyses of the resulting data indicate that recombination between strains is much more common than previously thought, even between strains from different biovars and thus with different tissue tropisms. Moreover, organisms were capable of swapping whole ompA genes. “In particular, recombination between ocular and urogenital strains appears to be relatively frequent,” the team notes, “correlating with reports of both cross-site and mixed infections of ocular and urogenital serotypes.”

    And while it has previously been thought that recombination is limited to a few hotspots in the Chlamydia chromosome, the latest data suggest that recombination occurs throughout the whole genome. “The clinical importance of our findings is extensive,” the authors conclude. “We have shown clear examples in which the genetic backbone of the strain is unlinked from its serotype.”

    Interestingly, the data in addition showed that genetic exchange and homologous recombination can occur within the DNA of the bacterial cryptic plasmid, indicating that using Chlamydia plasmid as a basis for diagnosis and strain typing may not be accurate.

    They suggest that replacement and chimerism of ompA probably represents a process of diversification by Chlamydia to prevent the host’s immune system from recognizing and fighting off an immediate second infection. What this means is that sequencing ompA, which is the main chromosomal diagnostic target used to detect C. trachomatis infections and to type their strains, is not a good way of determining genetic relatedness within the species.

    “Multilocus typing schemes, particularly those that are based on housekeeping genes under low selective pressure, more closely reflect the genome phylogeny and may prove useful in cases where the ulti­mate resolution of genome-wide SNP-based techniques is not neces­sary,” the investigators suggest. Such approaches must, however, be based on large enough numbers of loci such that the results aren’t confused by recombination. 


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