7th January 2008

Changing patterns of infection

Chlamydia trachomatis genome sheds light on an emerging infection

Chlamydia

Distribution of predicted and functional coding sequences shared between <em>C. trachomatis strains</em> L2, UW-3 and Har-13.

Researchers have decoded the genome of the strain of Chlamydia that causes the most severe, invasive form of the disease. Their study shows that, despite recent increases in invasive infections, the strain has remained virtually unchanged for 40 years.

Chlamydia is the most common treatable bacterial sexually transmitted disease worldwide, with around 90 million cases each year. As well as a sexually transmitted disease (most often infections of the cervix or urogenital tract), it causes eye infection (trachoma), and also invasive disease called lymphogranuloma vernerum (LGV). Remarkably, these very different infections are caused by strains of Chlamydia that are very similar to one another.

" We found no evidence that this is a new epidemic isolate that is spreading worldwide: LGV is an old strain causing a new disease "

Dr Nick Thomson

"Chlamydia trachomatis has almost 900 genes and we found fewer than ten that differed significantly between the trachoma and the LGV strains," says Dr Nick Thomson from the Wellcome Trust Sanger Institute, who led the sequencing effort. "Some genes have decayed in the LGV strain, but the genes that are common to all are almost identical. The very different behaviours are shaped by small-scale mutations in DNA sequence."

The study is published in the January 2008 issue of Genome Research by researchers from the Wellcome Trust Sanger Institute, the University of Southampton Medical School, Southampton HPA, University College Hospital, London and the University of California at Berkeley. Although the team found only a few sequence variants among the strains, they suggest that these key differences could provide new markers for improved diagnosis. For example, they confirmed that there were variants in each strain in a gene called Tarp that can be used to distinguish different isolates of LGV strains.

The most significant differences are thought to be those found in genes that alter the surface properties of Chlamydia, an organism that can replicate only inside host cells. To gain entry, Chlamydia must form close contact with the host cell and then trigger its uptake. Perhaps only two or three gene differences might markedly alter the ability of Chlamydia to prosper in different environments.

"Chlamydia are very difficult organisms to study in the laboratory and this, the first complete genome sequence for the invasive strain of Chlamydia trachomatis, will be of real value to research into and diagnosis of invasive Chlamydial infections," explains Professor Ian Clarke from the University of Southampton and senior author on the paper. "The gene catalogue will be of immediate use in designing studies to track Chlamydia and to understand the genes that cause these very different clinical consequences worldwide."

The researchers sequenced the genomes from two isolates of Chlamydia from patients with LGV - one obtained in California in the 1960s, and maintained as the major laboratory strain, and the other a recent isolate from a patient in London.

"The new sequences allow us to ask whether the recent increase in incidence of LGV is the result of emergence of a new and more virulent strain," continues Professor Clarke. "Our results suggest that the organism we find today is virtually identical with that isolated 40 years ago. It seems that we are not facing a novel, more dangerous organism."

The gene content of the two isolates is identical, with only around 500 differences between the two genomes. The research team found no evidence of novel genes or significant changes that might suggest a clear divergence between the two isolates. Only two changes, a small deletion and a single-letter change, are unique to the recent, London isolate.

Until recently, LGV was only rarely seen outside Africa or South-East Asia. However, in late 2004, more than 100 cases were reported in an outbreak in the Netherlands and, since that time, increasing numbers of cases have been seen in many countries. More than 400 cases were reported in the UK up to September 2006, in most cases among men who have sex with men.

"We found no evidence that this is a new epidemic isolate that is spreading worldwide," explains Dr Thomson. "Our results suggest that, far from being a novel and rapidly spreading form of Chlamydia, LGV is an old strain causing a new disease."

Chlamydia is, however, a wider health problem and accounts for 30 per cent of all new cases of sexually transmitted disease. Chlamydial infections are often symptomless for some time, increasing the chance of transmission. The UK Health Protection Agency suggested in November that "young sexually active adults should be screened for Chlamydia annually and after a partner change" because the highest at risk groups are young adults and gay men.

These genomes are the first to be published from the Wellcome Trust Sanger Institute using new-technology sequencing.

Notes to Editors

Publication details

  • Chlamydia trachomatis: genome sequence analysis of lymphogranuloma venereum isolates.

    Thomson NR, Holden MT, Carder C, Lennard N, Lockey SJ, Marsh P, Skipp P, O'Connor CD, Goodhead I, Norbertzcak H, Harris B, Ormond D, Rance R, Quail MA, Parkhill J, Stephens RS and Clarke IN

    Genome research 2008;18;1;161-71

Funding

This work was supported by grants from the Wellcome Trust to the Sanger Institute and by Wellcome Trust grant no. 080348 to Professor Clarke.

Chlamydia

In the UK, Chlamydia is the most commonly diagnosed STI with 113,585 confirmed cases in 2006, up by 4 per cent on 2005. Changes in patterns of infection are worrying new developments, including the increase in cases of LGV in gay men, and a mutated 'new variant' strain of C. trachomatis in Sweden that evades some of the main diagnostic tests.

Video

A short video of infection of cells by Chlamydia is available here. Researchers have decoded the genome of a strain of Chlamydia which causes the most severe form of this sexually transmitted disease.

They found that while Chlamydia strains can cause very different health problems, they are in fact remarkably similar to one another.

There is no sound on this video which is courtesy of David Barlow

Time lapse sequence showing infection by the aggressive LGV strain of C. trachomatis. These Chlamydia actively invade cells and grow within a specialized compartment taking over the host cells and destroying them.

Participating Centres

  • The Pathogen Sequencing Unit, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  • Chlamydia & Molecular Laboratory, Department of Clinical Microbiology, University College Hospital NHS Foundation Trust, The Windeyer Institute of Medical Sciences, London, UK
  • Molecular Microbiology Group, University Medical School, Southampton General Hospital, Southampton, UK
  • Health Protection Agency South East, Southampton General Hostpital, Southampton, UK
  • Centre for Proteomic Research, School of Biological Sciences, University of Southampton, Southampton, UK
  • School of Public Health, University of California, Berkeley, CA 94720, USA

University of Southampton

The University of Southampton is a leading teaching and research institution with a global reputation for research and scholarship. One of the UK's top 10 research universities, Southampton offers first-rate opportunities and facilities for study and research across a wide range of subjects in health, humanities, science and engineering. Established in 1971, the University of Southampton's School of Medicine is at the forefront of medical and basic science research. One of UK's leading medical schools for research income and high-quality outputs, it is committed to academic excellence in all aspects of medical education and research.

The School is internationally renowned for research in Cancer Sciences, Clinical Neurosciences, Community Clinical Sciences, Developmental Origins of Health and Disease, Human Genetics and Infection, Inflammation and Repair.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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The Wellcome Trust

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.

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