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
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
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
"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