Undercover Infective - Cracking the Code of a Quiet Killer

If you wanted to make sure you could hide while living amongst your enemies, what would you do? Learn to be a master of disguise and change your disguise frequently. Establish a seemingly intimate relationship with them. And not kill too many.

Dr Axel von Herbay

False-colour image of Tropheryma whipplei in which the genome is represented by the yellow-coloured regions.

But now some of agent T. whipplei‘s secrets have been stripped bare by researchers working at the Wellcome Trust Sanger Institute in Cambridgeshire, and colleagues in the UK, the US and Germany and it is hoped this will help explain how other pathogens survive and proliferate.

In a landmark publication in The Lancet (22 February 2003), they reveal the mechanisms by which Tropheryma whipplei hides from our defences. In this one project, the number of known genes in this enigmatic organism has grown from a handful to 784.

Although T. whipplei appears to cause only few cases of disease and has a particularly small genome, it is a remarkable lesson in how nature can work to mould organisms to their environments and how rapid change might occur. T. whipplei carries a set of DNA sequences unlike anything previously seen in bacterial genomes from which it appears to select ‘new’ regions that it weaves into the genes that encode its outer coating.

“This really is a wolf in sheep’s clothing. Within this amazingly small genome, it has packed a sophisticated array of tools to escape our defence mechanisms. It’s an incredibly adept operator which can tell us a great deal about bacteria and their evolution.”

Dr Stephen Bentley Who led the team at The Wellcome Trust Sanger Institute

As well as a shimmering, changing set of proteins encoded by its own genome, T. whipplei also appears to cloak itself in membranes stripped from the host cells, further reducing its appearance as a foreign invader.

“Unlike its closest known relatives which are soil-oriented organisms, T. whipplei has chosen a lifestyle that is based upon an intimate relationship with humans. This relationship is also characterized by bacterial dependence on host, long-term bacterial persistence, and an unusual blunted host response. For nearly 100 years this organism and its host relationship have remained poorly understood. In revealing its genetic blueprint we learn a great deal about the particular strategy chosen by T. whipplei for establishing this kind of relationship, and why it has been so difficult to cultivate in the absence of human cells, as well as novel mechanisms for generating genetic variability and unexpected features of actinomycete evolution.”

Dr David Relman Associate Professor of Microbiology & Immunology, and of Medicine at Stanford University

Even with the genome sequence, and a prediction of all the proteins it can make, T. whipplei still remains somewhat of an enigma. It is not known how it is spread it is not even known how many cases of disease it causes. Whipple’s disease is marked by the vaguest of signs weight loss, diarrhoea and abdominal pain: the organism lives in the lining of the gut.

Advanced cases may die from heart disease or neurologic disease, which may occur up to 20 years later. Diagnosis remains difficult, but the genome sequence will make an array of new diagnostic tools available. Treatment once diagnosed is usually very effective, although relapses years later are quite common. Bizarrely, there is an 8:1 ratio of male:female infections.

“T. whipplei is an almost uncharted species in biology. We know so little. It thrives in humans with only a few proteins; it changes its appearance with amazing frequency; it hides from us in humans and in test tubes. The genome sequence is our finest microscope to study this remarkable organism.”

Dr Axel von Herbay Professor of Pathology at the University of Heidelberg

The organism can be only poorly grown in the test tube it took longer to grow the bacteria needed for the genome project than it did to sequence and analyse the genome itself. Even then it needs help T. whipplei can be grown only associated with human cells in the test tube.

The genome consists of 925,938 base-pairs containing a predicted 784 genes: five percent of the genome is composed of repeated DNA sequences, used to boost variation. Most bacterial genomes are 3-4 times as large, code for perhaps 3000 genes, and contain almost no repetitive DNA.

T. whipplei lacks the genes for many core functions such as a major energy-generating system (the TCA cycle) and synthesis of key amino acids (arginine, tryptophan, histidine). It must scavenge many vital compounds from the environment.

More information

1. Participants

   • The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, is one of the world’s leading genome sequencing centres. Both the Sanger Institute and the Wellcome Trust have been at the forefront of efforts to keep sequence data in the public domain. The Institute employs nearly 600 people in the purpose-built campus at Hinxton, near Cambridge, UK. AS well as being a leading partner in the Human Genome Project sequencing one-third of the human genome sequence the Institute participates in national and international projects to sequence the genomes of disease-causing organisms. Currently it is sequencing or analysing the genomes of some 40 organisms.

   • Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For more information, please visit the Web site of the medical center’s Office of News and Public Affairs at http://mednews.stanford.edu.

   • The School of Biosciences at the University of Birmingham constitutes one of the larger university-based Bioscience research institutions in the country with a teaching staff in excess of 60. The School was awarded 5 in the recent Research Assesment Exercise. Research activities span from biophysics to ecology.

   • The Department of Pathology at the University of Heidelberg.

2. About T. whipplei

   Originally described in 1907 by George H Whipple, Whipple’s disease remained without a cause for 50 years, when rod-shaped bacteria were seen for the first time in 1961 by electron microscopy. However, these could not, until very recently, be grown in culture. Diagnosis remained very difficult until the advent of DNA-based methods in the 1990s.

   The causative organism is Tropheryma whipplei, closely related to no known organism, but placed in the same group (Actinobacteria) as the organisms that cause TB and leprosy and the soil-dwelling microbe, Streptomyces coelicolor, all of which have been sequenced at The Wellcome Trust Sanger Institute.

   Clinically, patients present most often with intestinal symptoms: diarrhoea, abdominal pain and weight loss, as well as swollen lymph nodes and arthritis. The disease is regarded as invariably fatal without treatment: the disease progresses to involve, typically, the central nervous system or the heart. Treatment with antibiotics is usually effective in the early stages. Even with treatment, relapses are common.

   The mode of spread is unknown, but assumed to be oral, given the residence of the organism primarily in the gut. The highest concentrations of organisms are found in the lining of the small intestine. It is still unclear whether a proportion of the healthy population may carry/carries the organism.

3. Websites

   • The Lancet website http://www.thelancet.com/
   • Sanger Institute T. whipplei pages https://www.sanger.ac.uk/Projects/T_whipplei/
   • The Wellcome Trust website http://wellcome.org/
   • Whipple’s Disease Online http://www.WhipplesDisease.net/
   • ‘Bug of the Month’ at Mt Sinai Hospital, Toronto http://microbiology.mtsinai.on.ca/bug/TW/tw-mm.shtml
   • Dr Relman’s lab website http://relman.stanford.edu/