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Killer Bug Tamed
TB bacteria can be rendered
less virulent, reports Biplab Das
The tenacity of the tuberculosis bacterium makes it one of the worst enemies of humans. One third of the world's population harbours it. An estimated two million people succumb to it every year. Shortly after taking refuge in a host's body, it develops a friendly relation with the immune system. This strategy has long intrigued tuberculosis researchers.
Two groups, one from Stanford University and the other from Albert Einstein College of Medicine in New York City, have cracked the secret. According to a report published in
Science, microbiologist Stanley Falkow of Stanford University and William Jacobs of Albert Einstein College of Medicine have identified genes that cause persistence of TB infection. These genes could help design new drugs.
The Stanford team resorted to the animal TB model. In frogs Mycobacterium marinum causes tuberculosis. It is a close cousin of the TB bacillus,
M. tuberculae. When infected with M. marinum, frogs develop a cluster of immune cells called
granulomas. Like human TB,
M. marinum, causes latent infection in frogs.
They needed to isolate those genes that allowed M. marium to persist. To do this,
Falkow and his teammates tagged the genes randomly with fluorescent protein. Then, they inserted the tagged genes into plasmids (circular pieces of DNA) of bacteria. If the persistent gene became active, the fluroscent protein would glow green.
Using this method, Falkow and his colleagues homed in on a dozen genes that
M. marium employs to reside in frogs' granulomas. They remain active when
M. marium roams freely. They also found some counterparts of
M. marium's genes in M. tuberculae. Two of the M. marium genes identified belong to the family of genes called
PE-PGRS that constitute 5 to 10 per cent of the
M. tuberculae genome. These genes code for peculiar proteins that consist of hundreds of glycines (the simplest amino acid).
The Stanford team removed one of the PE-PGRS genes in the frog bacterium. When this mutated bacteria was delivered into lab-nourished macrophages, the mainstay of the immune system in
granulomas, bacterial growth was halted. In frogs too, they grow poorly.
This proved the PE-PGRS family's role in the persistence of TB germs. "This is the only demonstration that these genes have any function," said Eric Rubin, a microbiologist at the Harvard School of Public Health in Boston. Ian
Orme, a TB researcher at Colorado State University in Fort Collins, came up with a noteworthy view. To him, the frog model is a poor one, in part because
M. marium is not hostile to mammals and must be injected in large doses to produce infection in frogs.
"I am not arguing that frogs are people. But marium and tuberculae have many things in common. One of them is a common pathogenic apparatus," defended
Falkow. He now needed to find out whether PE-PGRS genes had a role in M. tuberculae's virulence.
William Jacobs and his colleagues at Albert Einstein College of Medicine developed a way to support Falkow's research. Jacobs began his work with the safer organism Bacillus Calmette Guerin
(BCG), used as TB vaccine.
Bacteria are known to be virulent when they colonise. Jacobs and his colleagues' goal was to detect the genes that hold them together. They began to remove genes from
BCG. After a tireless search, they found a gene that normally makes an enzyme called cyclopropane synthase disrupting bacteria's ability to unite.
After this, they proceeded to switch off the same gene in M.
tuberculae. Initially, they took six months to remove it, but after a new technique was developed by Stoyan Bardorov of Einstein College, it was accomplished within three weeks. The mutant TB strain not only failed to unite, it also became less virulent.
Jacobs's team found that control animals infected with unaltered microbes survived for seven months and then died from infection. On the other hand, mutant microbes proliferated rapidly in the host, but after a few weeks, all the microbes died, sparing the lives of the laboratory mice.
"These results showed that the mutated enzyme plays a pivotal role in the survival and persistence of
M. tuberculae," said Jacobs. For both groups, the pressing task is to find out more about the TB bacteria's virulence and persistence.
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