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Sequencing Study Suggests Serotype-Based Chlamydia Classification Misleading

By Andrea Anderson

NEW YORK (GenomeWeb News) – The tests commonly used to classify Chlamydia trachomatis are often insufficient for understanding the real relationships between strains, according to a new genomics-based phylogenetic analysis that identified extensive recombination within and between C. trachomatis biovars.

As they reported online yesterday in Nature Genetics, researchers from the UK, Europe, Africa, and North America did whole-genome sequencing on three-dozen clinical C. trachomatis isolates collected in around the world over five decades.

Through a phylogenetic analysis involving the newly sequenced isolates and 16 more isolates sequenced previously, they uncovered examples of recombination at sites across the genome in C. trachomatis strains involved in eye infections, urogenital infections, and systemic infections — including sequence swapping at sites typically used for typing C. trachomatis.

"In terms of the [strains] that are commonly circulating, Chlamydia is a lot more dynamic than we ever previously thought," senior author Nicholas Thomson, a pathogen genomics researcher at the Wellcome Trust Sanger Institute, told GenomeWeb Daily News. "And dynamic in a bacterial population generally means more adaptable or more able to cope with change, selection, and so on."

Chlamydia bacteria are perhaps best known for their role in sexually transmitted infections. Indeed, urogenital infections caused by C. trachomatis are some of the most commonly diagnosed STIs around the world. But C. trachomatis is also responsible for tens of millions of cases of trachoma, an infectious eye disease that can lead to blindness.

And while ocular and some urogenital C. trachomatis strains cause localized infections, serotypes from the so-called lymphogranuloma venereum, or LGV, biovar have been associated with sexually transmitted systemic infections characterized by ulcerous sores and bubos.

Though most infections involving LGV serotypes are found in developing countries, an outbreak of a bubonic disease in Europe, North America, and Australia has been linked to a C. trachomatis LGV serotype called L2b.

Nevertheless, much is unknown about the Chlamydia strains circulating globally, the genetic relationships between these strains, and the specific symptoms associated with each, Thomson explained.

That's because most C. trachomatis typing has focused on a bacterial cell surface protein called major outer membrane protein, known as MOMP, or on the ompA gene that codes for this antigen.

"Our whole understanding of Chlamydia is really based on serotype," Thomson said, noting that it is now clear that serotype may provide only limited information about clinical features associated with a given strain or about disease change and spread over time.

Researchers had already characterized the genomes of representative ocular, urogenital, and LGV strains, he added, but large-scale genomic analyses have been slow to come to fruition due to the challenges associated with culturing enough of the bacteria to get genomic DNA for sequencing.

For the current study, he and his collaborators sequenced the genomes of 36 C. trachomatis isolates collected around the world between 1959 and 2009. These included a dozen L2b epidemic strains from the UK, Europe, or Canada; six other LGV strains from the US and South Africa; 14 urogenital strains from the UK, US, and Sweden; and four ocular strains from Tanzania.

To round out their phylogenetic analysis, the team also added in genetic data on 16 strains sequenced in the past, including two LGV strains, 11 urogenital infection-associated strains, and three ocular infection strains.

Their phylogenetic analysis pointed to three lineages: one comprised of LGV strains and another containing two urogenital clades — one with a branch leading to ocular isolates.

Contrary to what many had expected for C. trachomatis, the genomic profiles revealed extensive mixing and matching between the isolates, both within and between the ocular, urogenital, and LGV groups.

While C. trachomatis was known to have the necessary genetic hardware for doing this sort of recombination, Thomson explained, it was long assumed that they didn't.

"We actually show that recombination occurs within clinical isolates — not just laboratory isolates, but within circulating clinical isolates," Thomson said, adding that this recombination was found in all types of Chlamydia in "almost any combination that you can think of."

"The reality is that there are no physical barriers to recombination," he added. "All of these strains are recombining with each other."

Even more surprising from an epidemiological perspective was that some of these recombination events involved the gene coding for the MOMP antigen. In fact, the team saw several examples of bugs with the same ompA sequences being spread over diverse branches of the phylogenetic tree, suggesting this serotyping marker is not particularly good for sub-dividing Chlamydia into related groups.

"Serotype is not a good marker of phylogeny — of evolutionary history," Thomson said, noting that this may partly explain why it's been so difficult to consistently link clinical symptoms of C. trachomatis infection to specific serotypes.

The rampant rearrangement amongst strains also produced a clinical LGV isolate from Sweden that had initially been misdiagnosed because it had jettisoned part of a plasmid targeted by some diagnostic tests for Chlamydia.

"In the past, we didn't think the plasmid could be exchanged," Thomson said. "But in this paper we have evidence now … that even the plasmid can be exchanged."

In most cases, the new findings won't affect the way chlamydial infections are diagnosed and treated, he said, since the primary concern in the clinic is usually determining whether C. trachomatis is present or not.

But the research is expected to have immediate implications for the way C. trachomatis strains are tracked and studied in the future.

For their part, he and his colleagues plan to look more closely at the rate of recombination in C. trachomatis.

They are also collaborating with groups around the world to bring together and sequence as many additional clinical isolates as possible — an effort they hope will provide a better understanding of Chlamydia patterns of transmission, as well as some of the genetic patterns associated with specific clinical features.

"What we hope to do is use the resolution we've got to start asking very complex questions about the differences in disease manifestation, for example," Thomson said. "This provides a framework for doing that."

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