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.
That is exactly the classic strategy that enables a tiny bacterial cell to cause mayhem in the human body. Tropheryma whipplei is a master of disguise that inveigles a way into the enemy territory, settles down among the unsuspecting host trying, first and foremost, to survive and multiply and occasionally breaking out to cause illness.
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.
Dr Stephen Bentley, who led the team at The Wellcome Trust Sanger Institute, said, '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.'
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.
Dr David Relman, Associate Professor of Microbiology & Immunology, and of Medicine at Stanford University, said, '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.'
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.
Dr Axel von Herbay, Professor of Pathology at the University of Heidelberg, said, 'T. whippelii 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.'
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: 5 per cent 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.