Scientists discover gene that keeps TB asleep

By Redazione

EU funded researchers have identified a gene that determines whether the bacteria which causes tuberculosis will remain dormant in the body or develop into the active version of the disease,
the discovery could lead to the development of new drugs against the disease, which kills more people than any other bacterial infection.

According to the World Health Organisation (WHO), a third of the world’s population is infected with Mycobacterium tuberculosis, and up to 10 million new cases develop annually, 20% of which
lead to death. However, many people do not develop the disease immediately upon infection with the bacteria. Instead, the bug remains dormant in the body, enclosed in a capsule which the host
organism creates to protect itself.

It may remain in this state for years, or even decades, before becoming active and triggering the development of the disease. This often happens when the host’s immune system is weakened, by
poor nutrition or a disease of the immune system such as HIV, for example.

In this latest piece of research, scientists from the Max Planck Society in Germany and Yonsei University in South Korea investigated the dormant state of the bacteria and the mechanisms which
cause it to wake up and become active again. Their findings are published in the journal Cell Host and Microbe.

They focused their efforts on two variants of the disease that differ in one crucial aspect; while strain H37Rv causes the development of the disease, strain H37Ra is harmless, remaining
dormant in the host’s cells.

‘The different behaviour of the two strains is caused by minute genetic differences,’ explained Professor Stefan Kaufmann of the Max Planck Society’s Department of Immunology. The scientists
discovered that these differences could be traced back to a single mutation in a gene which codes for the protein PhoP in the harmless H37Ra strain.

‘An intact PhoP is therefore clearly necessary for the bacteria to be able to cause tuberculosis,’ commented Professor Kaufmann. PhoP is a transcription factor, which binds to the DNA and so
controls the activity of other genes. The mutated version of the gene lacked the ability to bind to the DNA correctly.

The next challenge for the scientists was to find out which genes PhoP controls. Their experiments led them to the so-called dormancy regulon, a group of genes that creates the proteins
responsible for initiating and maintaining the dormant state. In the harmless H37Ra strain, these genes were far more active than in the virulent H37Rv strain.

‘Probably the intact PhoP suppresses the genes of the dormancy regulon and so causes the bacteria to wake up,’ speculates the professor. A defective version of the protein makes the bacteria
less dangerous because it prevents it from waking up.

‘In any case we urgently need medicines, which attack the dormant bacteria,’ emphasised Professor Kaufmann. ‘Only in this way can we significantly reduce the unusually long treatment time of
six months. A more precise understanding of the survival strategies of the tuberculosis bacteria offer the first starting point for the development of new medicines, which are more urgently
needed than ever, as antibiotic-resistant tuberculosis bacteria are becoming more and more widespread.’

The work was supported by the EU-funded TB-VAC (‘Design and testing of vaccine candidates against tuberculosis’) project, which is funded under the ‘Life sciences, genomics and biotechnology
for health’ thematic area of the Sixth Framework Programme (FP6).

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