BioWorld International Correspondent
LONDON - The bacterium that causes leprosy contains so few functional genes that it is barely alive and in a constant state of starvation, an analysis of its genome suggests. These features probably explain why Mycobacterium leprae takes 14 days to divide, and why researchers have never been able to culture it in the laboratory.
Although the sequence of the genome of M. leprae may lead to new diagnostic tests for leprosy, pharmaceutical companies are unlikely to use the information to develop new drugs to fight the disease because few countries where leprosy occurs could afford to buy them.
Despite effective multidrug treatments and a vaccine, there are still almost 700,000 new cases of leprosy reported each year worldwide. In its most severe form, the disease causes damage to nerve cells and disfigurement.
Stewart Cole, head of the Unit of Bacterial Molecular Genetics at the Institut Pasteur in Paris, told BioWorld International: "Leprosy is a very mysterious disease in many ways because the organism which causes it cannot be cultured in the laboratory, making it very difficult to work with. Looking at the genome seemed to be a good way to figure out why this is so."
Cole, together with colleagues at the Institut Pasteur and from the Sanger Centre in Hinxton, UK, and the Veterinary Laboratories Agency in Addlestone, UK, report their findings in a paper in Nature titled "Massive gene decay in the leprosy bacillus."
The team found that the genome was "heavily degenerate," adding, "One of our main findings was that about 50 percent of the M. leprae genome did not appear to code for any protein, but when we looked at that 50 percent, we found that there were a number of dead genes in there which we could identify by comparison with M. tuberculosis, to which it is closely related. This was remarkable, because bacteria normally use more than 90 percent of their genome to code for proteins."
A large number of the genes that had been lost turned out to be ones involved in energy metabolism, or concerned with breaking down host molecules such as sugars, lipids and amino acids. "It looks as though M. leprae is unable to nourish itself, having only a borderline existence. It probably grows on a very restricted set of substrates," Cole said. This may explain, he said, why the organism grows so slowly - because it is starving.
Why should such changes have occurred during the bacterium's evolution? Cole suggests that the huge loss of genes could be a consequence of the organism's being an obligate pathogen, found only in human cells. It also could explain why leprosy, which was common throughout the world 600 or 700 years ago, has now disappeared from many areas.
While M. tuberculosis has about 4,000 genes and makes 1,800 soluble proteins, M. leprae has only about 1,600 intact genes and makes only about 400 soluble proteins. Of M. leprae's genes, about 1,200 are found in many other bacteria, which means that they are unlikely to play an important role in disease, Cole pointed out. "This leaves about 400 genes, of which 300 are found in both M. leprae and M. tuberculosis but not anywhere else and which are therefore good candidates for obligate mycobacterial functions. Then there are 100 or so genes specific for M. leprae, which are very interesting in terms of developing immunodiagnostic reagents, for example."
Better diagnostic tests are needed, Cole said, because the milder forms of leprosy are difficult to diagnose with current tests. Patients with milder leprosy could then be started on drug therapy earlier, reducing their ability to spread the infection to others, and lessening their risk of developing more severe forms of the disease after a few years.
The question of why and how M. leprae causes disease remains. Cole said: "To help us find this out, the fact that we have got a relatively small number of genes to work with is a considerable advantage. We can concentrate on these genes, which look like they are specific for leprosy and maybe some of them will turn out to be involved in invasion of nerves, or destruction of host cells, for example."
Although few pharmaceutical companies are likely to pour resources into developing a drug for a market that is almost exclusively limited to developing countries, Cole held out the hope that leprosy sufferers may benefit from spin-offs of research into drugs for tuberculosis. "Because M. leprae and M. tuberculosis are so closely related," he said, "the information contained in the genome of M. leprae will be of direct relevance to tuberculosis, so new drugs for leprosy may yet become available."