We killed it

THERE are some pathogens that disguise
themselves and prevent detection by the
host's immune system. There are others
that save themselves by mimicking the
defence molecules produced by the
host's body. Then there is the tuberculosis
bacterium.

Regarded as the world's most successful
infectious agent, the bacterium
Mycobacterium tuberculosis kills 1.3 million
people every year. 30 per cent of the
world's population is infected with the
MICROBIOLOGY: drug discovery
We killed it
TB bacterium plays dead,
immune cells are fooled
PHYSIOLOGY: energy conservation
The way you swing
A weight-loss tip: do not swing the arms while walking
bacterium, but the infected do not
know it; there are no symptoms. It is the
same when seen from a micro-scale: the
macrophages sent out by the human
body to kill it end up housing the
pathogen without realizing it.

Macrophages are white blood cells
that engulf and digest pathogens. They
swallow the tuberculosis bacterium with
the same intention but the bacterium
undoes their efforts. Once inside the
macrophage, it enters a near-dormant
state by controlling its growth rate. For
the macrophage it is as good as dead.
In this manner, the pathogen makes
a successful entry into the host's body.
What the bacterium does is control
the rate of formation of RNA from DNA.
This, in turn, controls the formation of
many proteins needed for growth and
development.

The team identified the key protein,
called CarD, that directs the bacterium
to act this way. This protein binds to a
an enzyme called the RNA polymerase
and inhibits the formation of RNA.
Hence CarD is the ticket to the bacte -
rium's survival in the host's body.

Glickman and his team found that
stress signalled the gene encoding for
the CarD protein to express the protein
in larger amounts. When scientists cultured
modified strains without the gene,
large numbers of bacteria died. In lab
cultures, the protein's absence made
them vulnerable to DNA damage, oxidative
stress and lack of nutrients. In
infected mice, absence of the protein led
the macrophages to kill their targets.

Targeting the CarD protein with
molecules that destroy its capabilities
might be just what TB drug manufacturers
should keep in mind.

The CarD protein is widely distributed
in the bacterial world. It is found in
Bacillus anthracis, the bacterium that
causes anthrax. "Hence this finding may
have broader applications in targeting
other important pathogens," said
Glickman. The study is in the July 10
issue of Cell.