TB bacteria missing genetic signposts for proteins during latent infection

21 November 2013

Tuberculosis, X-ray

Image: Coloured X-ray of the chest of a male patient with pulmonary tuberculosis (TB).©  GUSTOIMAGES/SCIENCE PHOTO LIBRARY

A third of the global population is thought to carry latent tuberculosis (TB) infection. In new research that may lead to novel antibiotics to treat TB, scientists have discovered that the process used by TB bacteria to translate many of their genes into proteins differs significantly from that of other commonly studied bacteria.

The study was led by Teresa Cortés and Douglas Young of the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute). Their team found that during latent TB infection, many genes were missing the typical sequences used to indicate where translation of a protein should begin.

Latent TB infection means a person is infected with Mycobacterium tuberculosis, the bacterium that causes TB, but does not have active disease. These people are not contagious.

However, there is a risk that latent infection can change into active disease at a later stage - this is more likely in certain circumstances, including alongside HIV infection, with treatment that affects the immune system (such as chemotherapy for cancer), or during malnutrition, such as in times of famine or civil war.

Dr Cortés explained: "We are interested in the way that M. tuberculosis carries out the fundamental biological process of translating RNA into proteins. We have found that, for a substantial proportion of the genes, this differs from the process used in commonly studied bacteria such as E. coli.

"A 'Shine-Dalgarno recognition sequence' is like a genetic signpost in an organism's DNA. It's a typical sequence found slightly upstream of a gene that tells a ribosome (the molecular machine that builds proteins from RNA) where to start translating that gene.

"These sequences are found in the genomes of many types of bacteria. However, in the TB bacterium, many of the messenger RNA molecules engage with ribosomes without using a conventional Shine-Dalgarno recognition sequence. These unusual 'leaderless' transcripts are particularly associated with genes that are thought to be required for persistent infection."  

For their study, the researchers used state-of-the-art sequencing technologies to carry out a complete characterisation of all the RNA molecules in an M. tuberculosis cell and to identify those that lack Shine-Dalgarno recognition sequences. They then compared the RNAs and proteins in actively growing cells compard with cells iin which growth was arrested by nutrient starvation (a model of latent infection).

Genes encoding proteins with active growth functions were markedly depleted from the transcripts of RNAs lacking Shine-Dalgarno recognition sequences. The scientists also found a significant increase in the overall representation of leaderless RNAs in the starvation model of latent infection.

"Our findings may help us to identify additional genes that contribute to the ability of M. tuberculosis to survive during prolonged latent infection prior to development of disease," added Dr Cortés. "The work could also lead to discovery of novel antibiotics that target non-conventional translation."

The NIMR scientists worked with colleagues at the Institute of Molecular Systems Biology in Zurich, Switzerland and the Centre for Public Health Research in Valencia, Spain. Their paper, Genome-Wide Mapping of Transcriptional Start Sites Defines an Extensive Leaderless Transcriptome in Mycobacterium tuberculosis, is published in Cell Reports.

  • Up to a third of the world's population are infected with tuberculosis (TB) but do not have active disease. This is known as latent infection. Medical Research Council scientists have discovered differences in the way the TB bacterium translates its genes into proteins when it's in the active disease state compared with during latent infection. 
  • DNA provides the genetic instructions for almost all living organisms. The genes found on an organism's DNA are first copied into molecules called messenger RNAs (known as transcription). These are then translated into the proteins that enable a cell to carry out its functions. This translation is carried out by molecular machines called ribosomes. 
  • This work is part of the SysteMTb Collaborative Project funded by the Framework Programme 7 of the European Commission. 
  • According to the WHO, TB is the second biggest killer due to a single infectious agent (after HIV/AIDS). In 2011, TB killed 1.4 million people and caused illness in 8.7 million.